Novel alkene oxindole derivatives

ABSTRACT

The present invention provides compounds of formula (I), 
     
       
         
         
             
             
         
       
     
     as well as pharmaceutical acceptable salt thereof, wherein R 1  to R 7  have the significance given herein. The compounds are useful in the treatment of prophylaxis of diseases that are related to AMPK regulation.

PRIORITY TO RELATED APPLICATION(S)

This application claims the benefit of International Patent ApplicationNo. PCT/CN2009/074060, filed Sep. 21, 2009, which is hereby incorporatedby reference in its entirety.

FIELD OF THE INVENTION

The invention relates to compounds which are activators of AMP-activatedprotein kinase (AMPK) and which are useful in the treatment orprophylaxis of diseases that are related to AMPK regulation, such asobesity, dyslipidemia, hyperglycemia, type 1 or type 2 diabetes.

BACKGROUND OF THE INVENTION

Obesity and type 2 diabetes, hypertension and cardiovascular disease,are diseases that feature serious disturbances in glucose and lipidmetabolism that severely affect the health and quality of life ofaffected individuals. The increasing prevalence of these diseases makesfinding new drug targets for treating this syndrome an urgent task.

AMP-activated protein kinase acts as a cellular energy sensor andregulator. It is activated by an increase in the cellular AMP:ATP ratioinduced by metabolic stress. Once activated, AMPK switches on catabolicpathways that generate ATP and switches off ATP-consuming anabolicpathways by acute regulation of the activity of key enzymes inmetabolism and chronic regulation of the expression of pivotaltranscription factors (Hardie, D G. Nature Reviews 8 (2007b), 774-785;Woods, A et al. Molecular and Cellular Biology 20 (2000), 6704-6711).The growing evidence of AMPK regulatory effects on glucose and lipidmetabolism makes it a potential drug target for treatment of diabetesand metabolic syndrome (Carling, D. Trends Biochem Sci 29(2004), 18-24;Hardie, D G. Annual Review of Pharmacology and Toxicology 47 (2007a),185-210; Kahn, B B et al. Cell Metabolism 1 (2005), 15-25; Long, Y C etal. The Journal of Clinical Investigation 116 (2006), 1776-1783).

At the physiological level, this concept has been supported by twoadipokines, leptin and adiponectin, both of which exert excellenteffects on glucose and lipid metabolism (Friedman, J M and Halaas, J L.Nature 395 (1998), 763-770; Muoio, D M et al. Diabetes 46 (1997),1360-1363; Yamauchi, T et al. Nature Medicine 7 (2001), 941-946). Recentstudies suggest that leptin and adiponectin exert their antidiabeticeffects by activating AMPK. Leptin stimulates muscle fatty acidoxidation by activating AMPK directly and through ahypothalamic-adrenergic pathway (Minokoshi, Y et al. Nature 415 (2002),339-343). Adiponectin stimulates glucose uptake and fatty acid oxidationin vitro by activation of AMPK. Furthermore, it exerts its hypoglycemiceffect by decreasing PEPCK and G6Pase expression, whereas theadministration of dominant negative α1 adenovirus reverses the effect invivo (Yamauchi, T et al. Nature Medicine 8 (2002), 1288-1295).

At the pharmacological level, the concept of AMPK as a potential targetfor treating metabolic syndrome has been further supported by thediscovery of two major classes of existing antidiabetic drugs:thiazolidinediones (rosiglitazone, troglitazone and pioglitazone) andbiguanides (metformin and phenformin) activate AMPK in cultured cellsand in vivo. Rosiglitazone is traditionally considered to be a PPARγagonist and exerts its antidiabetic effects through differentiation ofadipocytes (Semple, R K et al. The Journal of clinical investigation 116(2006), 581-589). Recent findings indicate that AMPK may be involved inthe antidiabetic effects of rosiglitazone (Brunmair, B et al. TheJournal of Biological Chemistry 277 (2002), 25226-25232; Kadowaki, T etal. The Journal of Clinical Investigation 116(2006), 1784-1792). In thecase of metformin, an existing antidiabetic agent without a definedmechanism of action, recent studies demonstrate that it could activateAMPK in vitro and in vivo by inhibiting complex I (El-Mir, M Y et al.The Journal of Biological Chemistry 275 (2000), 223-228; Owen, M R etal. The Biochemical Journal 348 Pt 3 (2000), 607-614; Zhou, G et al. TheJournal of Clinical Investigation 108 (2001), 1167-1174), and thehypoglycemic effect could be blocked completely by knockout of itsupstream kinase LKB1, confirming the key role of AMPK in mediating theantidiabetic effect of metformin (Shaw, R J et al. Science (New York)N.Y. 310 (2005), 1642-1646).

Most recently, Cool and coworkers have identified a small direct AMPKactivator, A-769662, which exerts antidiabetic effects in vivo (Cool, Bet al. Cell Metabolism 3 (2006), 403-416). Jia Li's laboratory hasidentified a small AMPK activator, PT1, which activates the inactiveforms of AMPK α2398 and α1394 with micromolar activity and exerts somecellular effects (Pang, T et al. The Journal of Biological Chemistry 283(2008), 16051-16060).

It has been found that the compounds of the present invention are potentAMPK activators. The compounds of the invention are therefore useful inthe treatment or prophylaxis of diseases that are related to AMPKregulation, such as obesity, dyslipidemia, hyperglycemia, type 1 or type2 diabetes.

SUMMARY OF THE INVENTION

The present invention relates to a compound of formula (I),

wherein

-   R¹ is selected from the group consisting of: hydrogen, halogen,    alkoxy, cyano, haloalkyl, alkylsulfanyl, aminosulfonyl,    alkylsulfonyl, haloalkoxy and alkylcarbonyl;-   R² is selected from the group consisting of: hydrogen, halogen,    alkoxy, cyano, haloalkyl, alkylsulfanyl, aminosulfonyl,    alkylsulfonyl, haloalkoxy and alkylcarbonyl;-   R³ is selected from the group consisting of: hydrogen, halogen,    alkoxy, cyano, haloalkyl, alkylsulfanyl, aminosulfonyl,    alkylsulfonyl, haloalkoxy and alkylcarbonyl;-   R⁴ is selected from the group consisting of: hydrogen, halogen,    alkoxy, cyano, haloalkyl, alkylsulfanyl, aminosulfonyl,    alkylsulfonyl, haloalkoxy and alkylcarbonyl;-   R⁵ is selected from the group consisting of: alkyl, hydroxyalkyl,    cycloalkyl, phenylalkyl, halophenylalkyl, phenyl, substituted    phenyl, thiophenyl and pyridinyl, wherein said substituted phenyl is    phenyl substituted with one to three substituents independently    selected from the group consisting of alkyl, alkoxy, halogen, cyano,    haloalkyl, alkylsulfanyl, aminosulfonyl, alkylsulfonyl, haloalkoxy    and alkylcarbonyl;-   R⁶ is selected from the group consisting of: alkyl, hydroxyalkyl,    cycloalkyl, phenylalkyl, halophenylalkyl, phenyl, substituted    phenyl, thiophenyl and pyridinyl, wherein said substituted phenyl is    phenyl substituted with one to three substituents independently    selected from the group consisting of alkyl, alkoxy, halogen, cyano,    haloalkyl, alkylsulfanyl, aminosulfonyl, alkylsulfonyl, haloalkoxy    and alkylcarbonyl;-   R⁷ is selected from the group consisting of: substituted phenyl,    pyridinyl, substituted pyridinyl, thiazolyl, substituted thiazolyl    and carboxy, wherein said substituted phenyl is phenyl substituted    with one to three substituents independently selected from the group    consisting of alkyl, hydroxy, alkoxy, carboxy, alkoxycarbonylalkyl,    alkylaminocarbonyl, carboxyalkoxy, alkoxycarbonyl,    alkoxycarbonylalkoxy and alkylsulfonylaminocarbonyl, and said    substituted pyridinyl and said substituted thiazolyl are,    respectively, pyridinyl and thiazolyl substituted with    alkoxycarbonyl or carboxy; and-   n is 0 or 1;    or a pharmaceutically acceptable salt or ester thereof;    with the provisos that:-   R⁵ and R⁶ are not both methoxyphenyl at the same time; and    when one of R⁵ and R⁶ is phenyl and the other one is phenyl,    methylphenyl or alkoxyphenyl, R⁷ is alkoxycarbonylphenyl.

The invention also relates to a pharmaceutical composition comprising acompound of formula I, or a pharmaceutically acceptable salt or esterthereof, and a therapeutically inert carrier.

The invention also relates to a process for the manufacture of thesenovel compounds and medicaments containing them.

The compounds of the invention have an activation effect on AMP(adenosine monophosphate)-activated protein kinase, which results inlowered blood glucose. The invention thus also concerns the use of suchcompounds for the treatment or prophylaxis of diseases that are relatedto AMPK regulation, such as obesity, dyslipidemia, hyperglycemia, type 1or type 2 diabetes.

DETAILS DESCRIPTION OF THE INVENTION

The present invention relates to a compound of formula (I),

wherein

-   R¹ is selected from the group consisting of: hydrogen, halogen,    alkoxy, cyano, haloalkyl, alkylsulfanyl, aminosulfonyl,    alkylsulfonyl, haloalkoxy and alkylcarbonyl;-   R² is selected from the group consisting of: hydrogen, halogen,    alkoxy, cyano, haloalkyl, alkylsulfanyl, aminosulfonyl,    alkylsulfonyl, haloalkoxy and alkylcarbonyl;-   R³ is selected from the group consisting of: hydrogen, halogen,    alkoxy, cyano, haloalkyl, alkylsulfanyl, aminosulfonyl,    alkylsulfonyl, haloalkoxy and alkylcarbonyl;-   R⁴ is selected from the group consisting of: hydrogen, halogen,    alkoxy, cyano, haloalkyl, alkylsulfanyl, aminosulfonyl,    alkylsulfonyl, haloalkoxy and alkylcarbonyl;-   R⁵ is selected from the group consisting of: alkyl, hydroxyalkyl,    cycloalkyl, phenylalkyl, halophenylalkyl, phenyl, substituted    phenyl, thiophenyl and pyridinyl, wherein said substituted phenyl is    phenyl substituted with one to three substituents independently    selected from the group consisting of alkyl, alkoxy, halogen, cyano,    haloalkyl, alkylsulfanyl, aminosulfonyl, alkylsulfonyl, haloalkoxy    and alkylcarbonyl;-   R⁶ is selected from the group consisting of: alkyl, hydroxyalkyl,    cycloalkyl, phenylalkyl, halophenylalkyl, phenyl, substituted    phenyl, thiophenyl and pyridinyl, wherein said substituted phenyl is    phenyl substituted with one to three substituents independently    selected from the group consisting of alkyl, alkoxy, halogen, cyano,    haloalkyl, alkylsulfanyl, aminosulfonyl, alkylsulfonyl, haloalkoxy    and alkylcarbonyl;-   R⁷ is selected from the group consisting of: substituted phenyl,    pyridinyl, substituted pyridinyl, thiazolyl, substituted thiazolyl    and carboxy, wherein said substituted phenyl is phenyl substituted    with one to three substituents independently selected from the group    consisting of alkyl, hydroxy, alkoxy, carboxy, alkoxycarbonylalkyl,    alkylaminocarbonyl, carboxyalkoxy, alkoxycarbonyl,    alkoxycarbonylalkoxy and alkylsulfonylaminocarbonyl, and said    substituted pyridinyl and said substituted thiazolyl are,    respectively, pyridinyl and thiazolyl substituted with    alkoxycarbonyl or carboxy; and-   n is 0 or 1;    or a pharmaceutically acceptable salt or ester thereof;    with the provisos that:-   R⁵ and R⁶ are not both methoxyphenyl at the same time; and    when one of R⁵ and R⁶ is phenyl and the other one is phenyl,    methylphenyl or alkoxyphenyl, R⁷ is alkoxycarbonylphenyl.

The compounds of the invention have an activation effect on AMP(adenosine monophosphate)-activated protein kinase, which results inlowered blood glucose.

As used herein, the term “alkyl” alone or in combination signifies asaturated, linear- or branched chain alkyl group containing 1 to 8,preferably 1 to 6, more preferably 1 to 4 carbon atoms, for examplemethyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl and tert-butyl.Preferred “alkyl” groups are methyl, ethyl, isopropyl and tert-butyl.

The term “alkoxy” alone or in combination signifies a group alkyl-O—,wherein the “alkyl” is as defined above; for example methoxy, ethoxy,propoxy, isopropoxy, n-butoxy, i-butoxy, 2-butoxy and t-butoxy.Preferred alkoxy groups are methoxy and ethoxy and more preferablymethoxy.

The term “cycloalkyl” alone or in combination refers to a saturatedcarbon ring containing from 3 to 7 carbon atoms, preferably from 3 to 6carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl. A preferred cycloalkyl group is cyclohexyl.

The term “halogen” means fluorine, chlorine, bromine or iodine. Halogenis preferably fluorine or chlorine.

The term “carboxy” alone or in combination refers to the group —COOH.

The term “carbonyl” alone or in combination refers to the group —C(O)—.

The term “amino” alone or in combination refers to primary (—NH₂—),secondary (—NH—) or tertiary amino (—N—).

The term “alkylsulfanyl” alone or in combination refers to the group—S-alkyl.

The term “sulfonyl” alone or in combination refers to the group —S(O)₂—.

The compounds according to the present invention may exist in the formof their pharmaceutically acceptable salts. The term “pharmaceuticallyacceptable salt” refers to conventional acid-addition salts orbase-addition salts that retain the biological effectiveness andproperties of the compounds of formula (I) and are formed from suitablenon-toxic organic or inorganic acids or organic or inorganic bases.Acid-addition salts include for example those derived from inorganicacids such as hydrochloric acid, hydrobromic acid, hydroiodic acid,sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and thosederived from organic acids such as p-toluenesulfonic acid, salicylicacid, methanesulfonic acid, oxalic acid, succinic acid, citric acid,malic acid, lactic acid, fumaric acid, and the like. Base-addition saltsinclude those derived from ammonium, potassium, sodium and, quaternaryammonium hydroxides, such as for example, tetramethyl ammoniumhydroxide. The chemical modification of a pharmaceutical compound into asalt is a technique well known to pharmaceutical chemists in order toobtain improved physical and chemical stability, hygroscopicity,flowability and solubility of compounds. It is for example described inBastin R. J., et. al., Organic Process Research & Development 2000, 4,427-435; or in Ansel, H., et. al., In: Pharmaceutical Dosage Forms andDrug Delivery Systems, 6th ed. (1995), pp. 196 and 1456-1457. Preferredare the sodium salts of the compounds of formula (I).

“Pharmaceutically acceptable esters” means that compounds of formula (I)may be derivatised at functional groups to provide derivatives which arecapable of conversion back to the parent compounds in vivo. Examples ofsuch compounds include physiologically acceptable and metabolicallylabile ester derivatives, such as methoxymethyl esters, methylthiomethylesters and pivaloyloxymethyl esters. Additionally, any physiologicallyacceptable equivalents of the compounds of general formula (I), similarto the metabolically labile esters, which are capable of producing theparent compounds of general formula (I) in vivo, are within the scope ofthis invention. Preferred are the methyl and ethyl esters of thecompounds of formula (I).

Preferred is a compound according of formula (I) wherein R¹ is selectedfrom the group consisting of: hydrogen, halogen and alkoxy.

Further preferred is a compound of formula (I) wherein R¹ is selectedfrom the group consisting of: hydrogen, fluoro and chloro.

Still further preferred is a compound of formula (I) wherein R¹ ishydrogen.

A compound of formula (I) wherein R² is selected from the groupconsisting of: hydrogen, halogen and alkoxy is preferred.

Also preferred is a compound of formula (I) wherein R² is hydrogen orfluoro.

Also particularly preferred is a compound of formula (I) wherein R³ isselected from the group consisting of: hydrogen, halogen and alkoxy.

A compound of formula (I) wherein R³ is selected from the groupconsisting of: hydrogen, fluoro, chloro and methoxy is also preferred.

In particular, preferred is a compound of formula (I) wherein R³ ishydrogen.

Furthermore, preferred is a compound of formula (I) wherein R⁴ isselected from the group consisting of: hydrogen, halogen and alkoxy.

A compound of formula (I) wherein R⁴ is hydrogen or fluoro is preferred.

A compound of formula (I) wherein R⁵ is selected from the groupconsisting of: alkyl, halophenylalkyl, phenyl, substituted phenyl,thiophenyl and pyridinyl, wherein said substituted phenyl is phenylsubstituted with one to three substituents independently selected fromthe group consisting of alkyl, alkoxy, halogen, cyano, haloalkyl,alkylsulfanyl, aminosulfonyl, alkylsulfonyl, haloalkoxy andalkylcarbonyl is further preferred.

In particular, preferred is a compound of formula (I) wherein R⁵ isselected from the group consisting of: phenyl, chlorophenyl,methoxyphenyl, methylphenyl, cyanophenyl, trifluoromethylphenyl,chlorofluorophenyl, trimethoxyphenyl, difluorophenyl, dichlorophenyl,bromophenyl, chlorotrifluoromethylphenyl, methylsulfanylphenyl,aminosulfonylphenyl, methylsulfonylphenyl, thiophenyl, fluorophenyl,pyridinyl, bis(trifluoromethyl)phenyl, isopropylphenyl, neopentyl,isopentyl, methylcarbonylphenyl and tert-butyl.

Also preferred is a compound of formula (I) wherein R⁵ is halophenyl orcyanophenyl.

A compound of formula (I) wherein R⁵ is chlorophenyl or cyanophenyl isalso preferred.

Furthermore, preferred is a compound of formula (I) wherein R⁶ isselected from the group consisting of: alkyl, hydroxyalkyl, cycloalkyl,phenyl and halophenyl.

Moreover, a compound of formula (I) wherein R⁶ is alkyl or phenyl isalso preferred.

Further, a compound of formula (I) wherein R⁶ is isopropyl or phenyl isalso preferred.

In particular, preferred is a compound of formula (I) wherein R⁶ isselected from the group consisting of: methyl, phenyl, methoxyphenyl,chlorophenyl, neopentyl, isopropyl, cyclohexyl, hydroxypropyl andtert-butyl.

Particularly preferred is a compound of formula (I) wherein R⁷ isselected from the group consisting of: substituted phenyl, substitutedpyridinyl, substituted thiazolyl and carboxy, wherein said substitutedphenyl is phenyl substituted with one to three substituentsindependently selected from alkyl, hydroxy, alkoxy, carboxy,alkoxycarbonylalkyl, alkylaminocarbonyl, carboxyalkoxy, alkoxycarbonyl,alkoxycarbonylalkoxy and alkylsulfonylaminocarbonyl, and saidsubstituted pyridinyl and said substituted thiazolyl are, respectively,pyridinyl and thiazolyl substituted with alkoxycarbonyl or carboxy.

Also particularly preferred is a compound of formula (I) wherein R⁷ isselected from the group consisting of: carboxyphenyl,alkoxycarbonylphenyl and carboxypyridinyl.

A compound according of formula (I) wherein R⁷ is selected from thegroup consisting of: carboxyphenyl, methoxycarbonylphenyl andcarboxypyridinyl is further preferred.

Further preferred is a compound of formula (I) wherein R⁷ is selectedfrom the group consisting of: ethoxycarbonylphenyl,methoxycarbonylmethylphenyl, phenyl substituted with methyl andmethoxycarbonyl, carboxy, methoxycarbonylphenyl,ethoxycarbonylmethoxyphenyl, isopropylaminocarbonylphenyl,methoxycarbonylpyridinyl, ethoxycarbonylthiazolyl, methoxyphenyl,trihydroxyphenyl, hydroxyphenyl, carboxyphenyl, carboxymethoxyphenyl,carboxythiazolyl, carboxypyridinyl and methylsulfonylminocarbonylphenyl.

Also preferred is a compound of formula (I) wherein n is 1.

Particularly preferred is a compound of formula (I) selected from thegroup consisting of:

-   3-{2-Oxo-3-[1-phenyl-eth-(E)-ylidene]-2,3-dihydro-indol-1-yl}-benzoic    acid ethyl ester;-   (3-{2-Oxo-3-[1-phenyl-eth-(E)-ylidene]-2,3-dihydro-indol-1-yl}-phenyl)-acetic    acid methyl ester;-   2-Methyl-5-{2-oxo-3-[1-phenyl-eth-(E)-ylidene]-2,3-dihydro-indol-1-yl}-benzoic    acid methyl ester;-   [2-Oxo-3-(1-phenyl-ethylidene)-2,3-dihydro-indol-1-yl]-acetic acid;-   3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid methyl ester;-   3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-7-fluoro-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid methyl ester;-   3-(3-Benzhydrylidene-2-oxo-2,3-dihydro-indol-1-ylmethyl)-benzoic    acid methyl ester;-   3-{3-[1-(4-Methoxy-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid methyl ester;-   3-{2-Oxo-3-[1-phenyl-1-p-tolyl-meth-(E)-ylidene]-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid methyl ester;-   3-{3-[1-(4-Chloro-phenyl)-1-(2-methoxy-phenyl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid methyl ester;-   3-{3-[1-(4-Cyano-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid methyl ester;-   3-{2-Oxo-3-[1-phenyl-1-(4-trifluoromethyl-phenyl)-meth-(E)-ylidene]-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid methyl ester;-   3-{3-[1-(3-Chloro-4-fluoro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid methyl ester;-   3-{2-Oxo-3-[1-phenyl-1-(3,4,5-trimethoxy-phenyl)-meth-(E)-ylidene]-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid methyl ester;-   3-{3-[1-(3,4-Difluoro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid methyl ester;-   3-{3-[1-(3-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid methyl ester;-   3-{3-[1-(2-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid methyl ester;-   3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-5-fluoro-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid methyl ester;-   3-{3-[1-(3,5-Dichloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid methyl ester;-   3-{3-[1-(2,3-Dichloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid methyl ester;-   4-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid methyl ester;-   3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-5-methoxy-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid methyl ester;-   3-{3-[1-(2-Bromo-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid methyl ester;-   3-{3-[1-(2-Chloro-5-trifluoromethyl-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid methyl ester;-   3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-4-fluoro-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid methyl ester;-   3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-6-fluoro-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid methyl ester;-   3-{3-[1-(3-Bromo-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid methyl ester;-   3-{3-[1-(2-Methylsulfanyl-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid methyl ester;-   3-{7-Chloro-3-[1-(4-chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-5-fluoro-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid methyl ester;-   3-{2-Oxo-3-[1-phenyl-1-(3-trifluoromethyl-phenyl)-meth-(E)-ylidene]-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid methyl ester;-   3-{2-Oxo-3-[1-phenyl-1-(4-sulfamoyl-phenyl)-meth-(E)-ylidene]-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid methyl ester;-   3-{3-[1-(2-Methanesulfonyl-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid methyl ester;-   3-{2-Oxo-3-[1-phenyl-1-thiophen-3-yl-meth-(E)-ylidene]-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid methyl ester;-   3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid methyl ester;-   3-{3-[1-(4-Chloro-phenyl)-1-(4-trifluoromethyl-phenyl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid methyl ester;-   (4-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-phenoxy)-acetic    acid ethyl ester;-   3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-N-isopropyl-benzamide;-   6-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-nicotinic    acid methyl ester;-   2-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-thiazole-4-carboxylic    acid ethyl ester;-   3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-1-(4-methoxy-benzyl)-1,3-dihydro-indol-2-one;-   3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-1-(3,4,5-trihydroxy-benzyl)-1,3-dihydro-indol-2-one;-   3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(Z)-ylidene]-1-(3,4,5-trihydroxy-benzyl)-1,3-dihydro-indol-2-one;-   3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-1-(4-hydroxy-benzyl)-1,3-dihydro-indol-2-one;-   3-{3-[1-(4-chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid;-   3-{3-[1-(4-Fluoro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid;-   3-{3-[1-(4-Methoxy-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid;-   3-{3-[1-(4-Chloro-phenyl)-1-(2-methoxy-phenyl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid;-   3-{2-Oxo-3-[1-phenyl-1-(4-trifluoromethyl-phenyl)-meth-(E)-ylidene]-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid;-   3-{2-Oxo-3-[1-phenyl-1-(2-trifluoromethoxy-phenyl)-meth-(E)-ylidene]-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid;-   3-{3-[1-(3-Chloro-4-fluoro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid;-   3-{2-Oxo-3-[1-phenyl-1-(3,4,5-trimethoxy-phenyl)-meth-(E)-ylidene]-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid;-   3-{3-[1-(3-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid;-   3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-5-fluoro-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid;-   3-{3-[1-(3,5-Dichloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid;-   3-{3-[1-(2,3-Dichloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid;-   2-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid;-   4-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid;-   3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-5-methoxy-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid;-   6-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-nicotinic    acid;-   3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-4-fluoro-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid;-   3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-6-fluoro-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid;-   3-{3-[1-(2-Methylsulfanyl-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid;-   3-{2-Oxo-3-[1-phenyl-1-pyridin-3-yl-meth-(E)-ylidene]-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid;-   3-{3-[1-(2-Chloro-5-trifluoromethyl-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid;-   3-{3-[1-(3,5-Bis-trifluoromethyl-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid;-   3-{2-Oxo-3-[1-phenyl-1-(3-trifluoromethyl-phenyl)-meth-(E)-ylidene]-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid;-   3-{2-Oxo-3-[1-phenyl-1-(4-sulfamoyl-phenyl)-meth-(E)-ylidene]-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid;-   3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid;-   3-{3-[1-(4-Chloro-phenyl)-1-(4-trifluoromethyl-phenyl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid;-   (4-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-phenoxy)-acetic    acid;-   3-{3-[1-(4-Isopropyl-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid;-   3-{3-[1-(3,4-Difluoro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid;-   3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-7-fluoro-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid;-   3-{5-Chloro-3-[1-(4-chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid;-   3-{3-[1-(2-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid;-   2-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-thiazole-4-carboxylic    acid;-   3-{3-[4-Methyl-1-phenyl-pent-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid methyl ester;-   3-{3-[3,3-Dimethyl-1-phenyl-but-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid methyl ester;-   3-{3-[2-(4-Chloro-phenyl)-1-phenyl-eth-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid methyl ester;-   3-{3-[3,3-Dimethyl-1-phenyl-but-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid methyl ester;-   3-{3-[4-Methyl-1-phenyl-pent-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid;-   3-{3-[1-(4-Chloro-benzyl)-2-methyl-prop-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid;-   3-{3-[1-(4-Fluoro-phenyl)-eth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}benzoic    acid;-   3-{3-[1-(4-Chloro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid methyl ester;-   3-{3-[2-Methyl-1-phenyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid methyl ester;-   3-{3-[1-(4-Acetyl-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid methyl ester;-   3-{3-[1-(4-Chloro-phenyl)-1-cyclohexyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid methyl ester;-   3-{3-[2-Methyl-1-(4-trifluoromethyl-phenyl)-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid methyl ester;-   3-{3-[1-(4-Chloro-phenyl)-2-hydroxy-2-methyl-prop-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid methyl ester;-   3-{3-[1-(4-Cyano-phenyl)-2-hydroxy-2-methyl-prop-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid methyl ester;-   3-{3-[1-(4-Chloro-phenyl)-2,2-dimethyl-prop-(Z)-ylidene]-3-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid methyl ester;-   3-{3-[1-(4-Cyano-phenyl)-2,2-dimethyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid methyl ester;-   3-{3-[1-(4-Chloro-phenyl)-2,2-dimethyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid methyl ester;-   3-{3-[1-(4-Chloro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid;-   3-{3-[1-(4-Cyano-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid;-   6-{3-[1-(4-Chloro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-pyridine-2-carboxylic    acid;-   6-{3-[1-(4-Cyano-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-pyridine-2-carboxylic    acid;-   3-{3-[1-(4-Chloro-phenyl)-2,2-dimethyl-prop-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid;-   3-{3-[1-(4-Cyano-phenyl)-2,2-dimethyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid;-   3-{3-[1-(4-Chloro-phenyl)-2,2-dimethyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid;-   3-{3-[1-(4-Fluoro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid;-   6-{3-[1-(4-Fluoro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-pyridine-2-carboxylic    acid;-   3-{3-[2-Methyl-1-pyridin-3-yl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid;-   3-{3-[1-(4-Chloro-phenyl)-1-cyclohexyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid;-   3-{3-[2-Methyl-1-(4-trifluoromethyl-phenyl)-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid;-   3-{3-[2-Methyl-1-thiophen-3-yl)-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid;-   3-{5-Chloro-3-[2-methyl-1-(4-trifluoromethyl-phenyl)-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid;-   3-{3-[1-(4-Acetyl-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid;-   N-(3-{3-[1-(4-Chloro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoyl)-methanesulfonamide;-   N-(3-{3-[1-(4-Chloro-phenyl)-2,2-dimethyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoyl)-methanesulfonamide;    and-   N-(3-{3-[1-(4-Chloro-phenyl)-2,2-dimethyl-prop-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoyl)-methanesulfonamide;    or a pharmaceutically acceptable salt or ester thereof.

Also particularly preferred is a compound of formula (I) selected fromthe group consisting of:

-   3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid;-   3-{3-[1-(4-Chloro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid;-   3-{3-[1-(4-Cyano-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic    acid;-   6-{3-[1-(4-Chloro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-pyridine-2-carboxylic    acid; and-   6-{3-[1-(4-Cyano-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-pyridine-2-carboxylic    acid;    or a pharmaceutically acceptable salt or ester thereof.

The compounds of the present invention can be prepared by anyconventional means. Suitable processes for synthesizing these compoundsare provided in the examples. Generally, compounds of formula (I) can beprepared according to the schemes illustrated below.

In the following schemes, Ar is phenyl, substituted phenyl, pyridinyl,substituted pyridinyl, thiazolyl or substituted thiazolyl, whereinsubstituted phenyl is phenyl substituted with one to three substituentsindependently selected from alkyl, hydroxy, alkoxy, carboxy,alkoxycarbonyl, alkoxycarbonylalkyl, alkylaminocarbonyl, carboxyalkoxy,alkoxycarbonylalkoxy and alkylsulfonylaminocarbonyl, wherein substitutedpyridinyl and substituted thiazolyl are pyridinyl and thiazolylsubstituted with alkoxycarbonyl or carboxy. R⁸ is independently selectedfrom the group consisting of alkyl, alkoxy, halogen, cyano, haloalkyl,alkylsulfanyl, aminosulfonyl, alkylsulfonyl, haloalkoxy andalkylcarbonyl as mono-substituent, bi-substituent or tri-substituent. R¹to R⁷ are as defined above unless otherwise indicated.

One method for synthesizing a compound of the invention is set forth inScheme 1, wherein the oxindole Ia is prepared. In this process, thecondensation reaction between the substituted oxindole II and thesubstituted acetophenone III gives the intermediate IV, whichsubsequently undergoes coupling reaction in the presence of copper saltcatalyst to produce compound Ia.

In the first step outlined in Scheme 1, intermediate IV can be preparedby a condensation reaction between the substituted oxindole II and thesubstituted acetophenone III. The reaction can be carried out in thepresence of an organic base such as piperidine or pyrrolidine, in anorganic solvent such as methanol, ethanol, toluene or the mixturethereof, under reflux overnight.

The intermediate IV couples with the aryl halide V to afford thecompound of formula Ia. The coupling reaction can be carried out in thepresence of a copper catalyst such as copper(I) iodide (CuI), incombination with a ligand such as 2,2′-bipyridine, proline,N,N′-dimethyl glycine or ethylene glycol, and a suitable base such assodium carbonate, potassium carbonate, cesium carbonate, sodiummethoxide, sodium tert-butoxide, potassium tert-butoxide, sodiumhydride, triethylamine, or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), ina suitable organic solvent such as acetonitrile, dichloromethane,tetrahydrofuran, toluene, benzene, 1,4-dioxane, N,N-dimethylformamide,dimethyl sulfoxide, N-methylpyrrolidinone or a mixture thereof, at atemperature between 100 and 180° C. for 15 to 60 minutes under microwaveirradiation. Alternatively, the reaction can be carried out at elevatedtemperature such as 80° C. for a longer reaction time without microwaveirradiation (Ley, S. V. et al., Angew. Chem. Int. Ed. 42 (2003) 5400).

The compound of formula Ib can be prepared according to Scheme 2. Inthis process, the condensation reaction between the compound IV and thecommercially available reagent VI gives the intermediate VII, whichsubsequently undergoes a hydrolysis reaction to afford the compound offormula Ib.

In the first step outlined in Scheme 2, starting material IV can beobtained through the synthetic method illustrated in Scheme 1. Theintermediate VII can be prepared by an alkylation reaction between VIand IV when using base such as sodium hydride, potassium carbonate orcesium carbonate in organic solvent such as tetrahydrofuran,N,N-dimethylformamide or the mixture thereof, at room temperature forseveral hours.

Finally, hydrolysis of the methyl ester VII affords the compound Ib.Hydrolysis of the methyl ester can be carried out in the presence of anaqueous inorganic base such as lithium hydroxide, sodium hydroxide orpotassium hydroxide in a solvent such as methanol, 1,4-dioxane ortetrahydrofuran at room temperature for several hours.

The compound of formula Ic can be prepared according to Scheme 3. Thisapproach is based on a highly efficient palladium-catalyzed synthesis ofasymmetrically substituted 3-(diarylmethylenyl)indolinone from readilyaccessible starting materials. This reaction can be carried outsuccessfully in the presence of catalytic amount of Pd(OAc)₂, usingN,N-dimethylformamide as solvent and NaOAc as a base. The reactionusually takes place at 110° C. and needs several hours to complete(Artur Pinto et al., Org. Lett. 4927, 2006). The amide X can be preparedby the coupling reaction between aniline VIII and carboxylic acid IX inthe presence of coupling reagent such as 1,3-dicyclohexylcarbodiimide.

Intermediate XII can be prepared by alkylation reaction between XI andX. The reaction usually needs sodium hydride, potassium carbonate orcesium carbonate as a base and is carried out at room temperature forseveral hours in organic solvent such as tetrahydrofuran orN,N-dimethylformamide.

XIV can be prepared by the method described in Scheme 3. Treatment ofXIV with boron tribromide in dichloromethane successfully affords Id.

XV can be prepared by the method described in Scheme 3. Hydrolysis of XVin a solvent such as methanol, 1,4-dioxane or tetrahydrofuran at roomtemperature for several hours in the presence of an aqueous inorganicbase such as lithium hydroxide, sodium hydroxide or potassium hydroxidesuccessfully affords acid Ie.

The compounds of formula If and Ig can be prepared according to Scheme6. This approach is based on Nickel catalyzed carboannulation reactionof zinc reagent XVII with unsaturated compound XVI (Ruixue Deng, et al.,Org. Lett. 5207, 2007).

The starting material XVI can be prepared according to the methoddescribed in Scheme 3.

The compounds of formula Ih and Ii can be prepared according to Scheme7. Hydrolysis of If and Ig in a solvent such as methanol, 1,4-dioxane ortetrahydrofuran at room temperature for several hours in the presence ofan aqueous inorganic base such as lithium hydroxide, sodium hydroxide orpotassium hydroxide successfully affords acids Ih and Ii.

The compounds of formula Ij can be prepared according to Scheme 8. Thekey step is the palladium catalyzedHeck-Carbocyclization/Suzuki-Coupling Reaction between iodide XVIII andboronic acid XIX in the presence of catalytic amount of Pd(PPh₃)₄. Thisreaction proceeds smoothly when using CsF or copperthiophene-2-carboxylic acid as base (Reiko, Y. et al., J. Org. Chem. 70,6972, 2005; Wing S. Cheung, et al., J. Org. Chem. 70, 3741, 2005).

Hydrolysis of XX in a solvent such as methanol, 1,4-dioxane ortetrahydrofuran at room temperature for several hours in the presence ofan aqueous inorganic base such as lithium hydroxide, sodium hydroxide orpotassium hydroxide successfully affords acid Ij.

The starting material XVIII can be prepared according to the proceduredescribed in Scheme 3.

The compounds of formula Ik can be prepared according to Scheme 9. Thekey step is the palladium catalyzedHeck-Carbocyclization/Suzuki-Coupling Reaction between iodide XXVI andboronic acid XXVII in the presence of catalytic amount of Pd(PPh₃)₄.This reaction proceeds smoothly when using CsF or copperthiophene-2-carboxylic acid as base (Reiko, Y. et al., J. Org. Chem. 70,6972, 2005; Wing S. Cheung, et al., J. Org. Chem. 70, 3741, 2005).

The amide XXVI can be prepared by the alkylation between amide XXIV andbenzyl bromide XXV as described in Scheme 3. Amide XXIV can be preparedby reacting isocyanate XXII with lithium reagent XXIII generated fromn-butyl lithium and acetylene. The isocyanate XXII can be prepared bytreating 2-iodo-anilines XXI with triphosgene in organic solvent such asdichloromethane in the presence of saturated aqueous sodium bicarbonatesolution.

The compounds of formula II can be prepared according to Scheme 10.Hydrolysis of ester Ik in a solvent such as methanol, 1,4-dioxane ortetrahydrofuran at room temperature for several hours in the presence ofan aqueous inorganic base such as lithium hydroxide, sodium hydroxide orpotassium hydroxide successfully affords acid I1.

The compounds of formula Im can be prepared according to Scheme 11.Treatment of acid I1 with methylsulfonamide in the presence of couplingreagent such as 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride and organic base such as DMAP for hours successfullyaffords compound Im.

The invention also relates to a process for the preparation of acompound of formula (I) comprising one of the following steps:

(a) the reaction of a compound according to formula (A)

in the presence R⁷—X and a copper catalyst;(b) the reaction of a compound according to formula (B)

in the presence of R⁸—I and a palladium catalyst;(c) the reaction of a compound according to formula (C)

in the presence of boron tribromide;(d) the reaction of a compound according to formula (D)

in the presence of R⁶—ZnBr and a nickel catalyst;(e) the reaction of a compound according to formula (E)

in the presence of a base;(f) the reaction of a compound according to formula (F)

in the presence of R⁸—B(OH)₂ and a palladium catalyst;(g) the reaction of a compound according to formula (G)

in the presence of MeSO₂NH₂ and a coupling reagent;wherein R¹ to R⁷ are as defined above, wherein Ar is selected from thegroup consisting of: phenyl, substituted phenyl, pyridinyl andthiazolyl, wherein substituted phenyl is phenyl substituted with one ortwo substituents independently selected from the group consisting of:alkyl, hydroxy, alkoxy, carboxy, alkoxycarbonylalkyl,alkylaminocarbonyl, carboxyalkoxy, alkoxycarbonyl, alkoxycarbonylalkoxyand alkylsulfonylaminocarbonyl, wherein R¹⁰ is phenyl substituted withone to three substituents independently selected from the groupconsisting of: alkyl, alkoxy, halogen, cyano, haloalkyl, alkylsulfanyl,aminosulfonyl, alkylsulfonyl, haloalkoxy and alkylcarbonyl, wherein R⁹is alkyl, wherein R¹¹ is alkyl and wherein X is chloro or bromo.

R⁹ is preferably methyl or ethyl. R¹¹ is preferably selected from thegroup consisting of: C₁-C₄ alkyl, preferably methyl and ethyl, morepreferably methyl.

The reaction of step (a) can be carried out in the presence of couplingreagent, such as a copper catalyst, such as copper(I) iodide (CuI), incombination with a ligand such as 2,2′-bipyridine, proline,N,N′-dimethyl glycine or ethylene glycol, and a suitable base such assodium carbonate, potassium carbonate, cesium carbonate, sodiummethoxide, sodium tert-butoxide, potassium tert-butoxide, sodiumhydride, triethylamine, or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), ina suitable organic solvent such as acetonitrile, dichloromethane,tetrahydrofuran, toluene, benzene, 1,4-dioxane, N,N-dimethylformamide,dimethyl sulfoxide, N-methylpyrrolidinone or a mixture thereof. Thereaction temperature can be for example between 100 and 180° C., e.g.for 15 to 60 minutes under microwave irradiation. Alternatively, thereaction can be carried out at a elevated temperature such as 80° C. fora longer reaction time without microwave irradiation.

The reaction of step (b) can be carried out in the presence of catalyticamount of Pd(OAc)₂, using N,N-dimethylformamide as solvent and NaOAc asa base. The reaction usually takes place at 110° C. and may need severalhours to complete.

Step (c) is preferably carried out in dichloromethane.

Step (e) can be carried out in a solvent such as methanol, 1,4-dioxaneor tetrahydrofuran, e.g. at room temperature for several hours. The baseis preferably an aqueous inorganic base such as lithium hydroxide,sodium hydroxide or potassium hydroxide.

The reaction of step (f) can be carried out in the presence of catalyticamount of Pd(PPh₃)₄. A base is preferably employed. This reactionproceeds smoothly when using CsF or copper thiophene-2-carboxylic acidas base.

The reaction of step (g) can be achieved in the presence of couplingreagent such as 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride and an organic base such as DMAP.

The invention also relates to a compound of formula (I) for use astherapeutically active substance.

The invention also relates to a pharmaceutical composition comprising acompound of formula (I) and a therapeutically inert carrier.

The use of a compound of formula (I) for the preparation of medicamentsuseful in the treatment or prophylaxis diseases that are related to AMPKregulation is an object of the invention.

The invention relates in particular to the use of a compound of formula(I) for the preparation of a medicament for the treatment or prophylaxisof obesity, dyslipidemia, hyperglycemia, type 1 diabetes or type 2diabetes, in particular type 2 diabetes.

Said medicaments, e.g. in the form of pharmaceutical preparations, canbe administered orally, e.g. in the form of tablets, coated tablets,dragées, hard and soft gelatine capsules, solutions, emulsions orsuspensions. The administration can, however, also be effected rectally,e.g. in the form of suppositories, or parenterally, e.g. in the form ofinjection solutions with an effective amount of a compound as definedabove.

The above-mentioned pharmaceutical composition can be obtained byprocessing the compounds according to this invention withpharmaceutically inert inorganic or organic carriers. Lactose, cornstarch or derivatives thereof, talc, stearic acids or its salts and thelike can be used, for example, can be used as such carriers for tablets,coated tablets, dragées and hard gelatine capsules. Suitable carriersfor soft gelatine capsules are, for example, vegetable oils, waxes,fats, semi-solid and liquid polyols and the like. Depending on thenature of the active substance no carriers are, however, usuallyrequired in the case of soft gelatine capsules. Suitable carriers forthe production of solutions and syrups are, for example, water, polyols,glycerol, vegetable oil and the like. Suitable carriers forsuppositories are, for example, natural or hardened oils, waxes, fats,semi-liquid or liquid polyols and the like.

The pharmaceutical composition can, moreover, contain preservatives,solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners,colorants, flavorants, salts for varying the osmotic pressure, buffers,masking agents or antioxidants. They can also contain still othertherapeutically valuable substances.

The dosage depends on various factors such as manner of administration,species, age and/or individual state of health. The doses to beadministered daily are about 5-400 mg/kg, preferably about 10-100 mg/kg,and can be taken singly or distributed over several administrations.

A compound of formula (I) when manufactured according to the aboveprocess is also an object of the invention.

Furthermore, the invention also relates to a method for the treatment orprophylaxis of diseases that are related to AMPK regulation, whichmethod comprises administering an effective amount of a compound offormula (I).

The invention further relates to a method for the treatment orprophylaxis of obesity, dyslipidemia, hyperglycemia, type 1 diabetes ortype 2 diabetes, in particular type 2 diabetes, which method comprisesadministering an effective amount of a compound of formula (I).

Furthermore, the invention also relates to a compound of formula (I) forthe preparation of medicaments useful in the treatment of cancers thatare related to AMPK regulation and provides a method for the treatmentof cancers that are related to AMPK regulation.

The invention is illustrated by the following examples which have nolimiting character. Unless explicitly otherwise stated, all reactions,reaction conditions, abbreviations and symbols have the meanings wellknown to a person of ordinary skill in organic chemistry.

EXAMPLES

Intermediates and final compounds were purified by flash chromatographyusing one of the following instruments: i) Biotage SP1 system and theQuad 12/25 Cartridge module, ii) ISCO combi-fiash chromatographyinstrument. Silica gel Brand and pore size: i) KP-SIL 60 Å, particlesize: 40-60 uM; ii) CAS registry NO: Silica Gel: 63231-67-4, particlesize: 47-60 micron silica gel; iii) ZCX from Qingdao Haiyang ChemicalCo., Ltd, pore: 200-300 or 300-400.

Intermediates and final compounds were purified by preparative HPLC onreversed phase column using X Bridge™ Perp G8 (5 um, OBD™ 30×100 mm)column or SunFire™ Perp C₁₈ (5 um, OBD™ 30×100 mm) column.

LC/MS spectra were obtained using a MicroMass Plateform LC (Waters™alliance 2795-ZQ2000). Standard LC/MS conditions were as follows(running time 6 min):

Acidic condition: A: 0.1% formic acid in H₂O; B: 0.1% formic acid inacetonitrile;

Basic condition: A: 0.01% NH₃.H₂O in H₂O; B: acetonitrile;

Neutral condition: A: H₂O; B: acetonitrile.

Mass spectra (MS): generally only ions which indicate the parent massare reported, and unless otherwise stated the mass ion quoted is thepositive mass ion (M+H)⁺.

The microwave assisted reactions were carried out in a Biotage InitiatorSixty.

NMR spectra were obtained using Bruker Avance 400 MHz.

All reactions involving air-sensitive reagents were performed under anargon atmosphere. Reagents were used as received from commercialsuppliers without further purification unless otherwise noted.

In case a mixture of E and Z isomers is produced during a reaction,these isomers are separated by methods described herein or known to theman skilled in the art such as e.g. chromatography or crystallization.

Example 13-[2-Oxo-3-(1-phenyl-ethylidene)-2,3-dihydro-indol-1-yl]-benzoic acidethyl ester

3-(1-Phenyl-ethylidene)-1,3-dihydro-indol-2-one

Oxindole (0.1332 g, 1 mmol) and acetophenone (1.4 ml, 1.2 mmol) weremixed in toluene; then pyrrolidine (0.17 ml, 2 mmol) was added. Themixture refluxed for 3 hand monitored by TLC. When the reaction wasfinished the solvent was removed under reduced pressure. The residue wasseparated by flash chromatography column (gradient elution, 10-25% ethylacetate in petroleum ether) to give3-(1-phenyl-ethylidene)-1,3-dihydro-indol-2-one as yellow powder (200mg, 85%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.70 (s, 3H) 5.96 (d, J=7.83Hz, 1H) 6.51-6.57 (m, 1H) 6.77 (d, J=7.58 Hz, 1H) 7.00-7.10 (m, 1H)7.30-7.37 (m, 2H) 7.44-7.58 (m, 3H) 10.54 (br. s., 1H). MS calcd. forC₁₆H₁₃NO 235, obsd. (ESI⁺) [(M+H)⁺]236.

3-[2-Oxo-3-(1-phenyl-ethylidene)-2,3-dihydro-indol-1-yl]-benzoic acidethyl ester

A Schlenk tube was charged with CuI (9.6 mg, 0.050 mmol, 5.0 mol %),3-(1-phenyl-ethylidene)-1,3-dihydro-indol-2-one (352.7 mg, 1.5 mmol),and K₂CO₃ (276 mg, 2.0 mmol), evacuated, and backfilled with argon.N,N′-dimethylethylenediamine (11 uL, 0.10 mmol, 10 mol %), ethyl3-iodobenzoate (278.8 mg, 1.01 mmol), and acetonitrile (1.5 ml) wereadded under argon. The Schlenk tube was sealed with a Teflon valve andthe reaction mixture was stirred at 80° C. for 23 h. The reaction wasmonitored by HPLC. When the reaction was finished, the solvent wasremoved under reduced pressure. The residue was separated by flashchromatography column (gradient elution, 5-10% ethyl acetate inpetroleum ether) to give3-[2-oxo-3-(1-phenyl-ethylidene)-2,3-dihydro-indol-1-yl]-benzoic acidethyl ester as yellow powder (344 mg, 90%). ¹H NMR (400 MHz, CDCl₃) δppm1.42 (t, J=7.20 Hz, 3H) 2.87 (s, 3H) 4.42 (q, J=7.07 Hz, 2H) 6.25 (d,J=7.58 Hz, 1H) 6.68-6.78 (m, 2H) 7.09 (t, J=7.71 Hz, 1H) 7.34-7.40 (m,2H) 7.47-7.58 (m, 3H) 7.62-7.72 (m, 2H) 8.11-8.19 (m, 2H). MS calcd. forC₂₅H₂₁NO₃ 383, obsd. (ESI⁺) [(M+H)⁺] 383.9.

Example 2(3-{2-Oxo-3-[1-phenyl-eth-(E)-ylidene]-2,3-dihydro-indol-1-yl}-phenyl)-aceticacid methyl ester

The title compound was prepared in analogy to Example 1 starting from(3-bromo-phenyl)-acetic acid methyl ester (commercially available) and3-[1-phenyl-eth-(E)-ylidene]-1,3-dihydro-indol-2-one. ¹H NMR (400 MHz,DMSO-d₆) δppm 2.77 (s, 3H) 3.65 (s, 3H) 3.81 (s, 2H) 6.08 (d, J=7.33 Hz,1H) 6.66-6.72 (m, 2H) 7.11 (t, J=7.33 Hz, 1H) 7.35-7.44 (m, 5H)7.51-7.61 (m, 4H).

Example 32-Methyl-5-{2-oxo-3-[1-phenyl-eth-(E)-ylidene]-2,3-dihydro-indol-1-yl}-benzoicacid methyl ester

The title compound was prepared in analogy to Example 1 starting from5-bromo-2-methyl-benzoic acid methyl ester (commercially available) and3-[1-phenyl-eth-(E)-ylidene]-1,3-dihydro-indol-2-one. ¹H NMR (400 MHz,chloroform-d) δppm 2.71 (s, 3H) 2.86 (s, 3H) 3.91 (s, 3H) 6.24 (d,J=7.83 Hz, 1H) 6.67-6.75 (m, 2H) 7.08 (t, J=7.83 Hz, 1H) 7.34-7.37 (m,2H) 7.43-7.47 (m, 1H) 7.49-7.56 (m, 4H) 8.05 (d, J=2.27 Hz, 1H).

Example 4 [2-Oxo-3-(1-phenyl-ethylidene)-2,3-dihydro-indol-1-yl]-aceticacid

3-(1-Phenyl-ethylidene)-1,3-dihydro-indol-2-one

The synthetic method of 3-(1-phenyl-ethylidene)-1,3-dihydro-indol-2-oneis described in Example 1.

[2-Oxo-3-(1-phenyl-ethylidene)-2,3-dihydro-indol-1-yl]-acetic acidmethyl ester

3-(1-Phenyl-ethylidene)-1,3-dihydro-indol-2-one (294 mg, 1 mmol) wasdissolved in anhydrous DMF, then methyl bromoacetate (184 mg, 1.2 mmol)was added. Finally, Cs₂CO₃ (488 mg, 1.5 mmol) was added in one portion.The mixture was stirred at room temperature overnight. The reaction wasmonitored by HPLC. When the reaction was finished, the solvent wasremoved under reduced pressure. The residue was separated by flashchromatography column (gradient elution, 5-10% ethyl acetate inpetroleum ether) to give[2-oxo-3-(1-phenyl-ethylidene)-2,3-dihydro-indol-1-yl]-acetic acidmethyl ester as yellow powder (230 mg, 75%). MS calcd. for C₁₉H₁₇NO₃307, obsd. (ESI⁺) [(M+1)⁺] 308.1.

[2-Oxo-3-(1-phenyl-ethylidene)-2,3-dihydro-indol-1-yl]-acetic acid

[2-Oxo-3-(1-phenyl-ethylidene)-2,3-dihydro-indol-1-yl]-acetic acidmethyl ester (50 mg, 0.16 mmol) was dissolved in menthol 1 ml; then 0.1ml water was added. Finally, lithium hydroxide (10 mg) was added. Themixture was stirred overnight. The reaction was monitored by HPLC. Whenthe reaction was finished, the solvent was removed under reducedpressure. The residue was dissolved in 2 ml DMF for prepared HPLC togive [2-oxo-3-(1-phenyl-ethylidene)-2, 3-dihydro-indol-1-yl]-acetic acidas white powder (11 mg). ¹H NMR (400 MHz, CDCl₃) δppm 2.82 (s, 3H) 4.61(s, 2H) 6.20 (d, J=7.58 Hz, 1H) 6.66-6.73 (m, 2H) 7.14 (t, J=7.58 Hz,1H) 7.31 (s, 2H) 7.46-7.54 (m, 3H). MS calcd. for C₁₈H₁₅NO₃ 293, obsd.(ESI⁺) [(M+H)⁺] 294.1.

Example 53-((3-((4-Chlorophenyl)(phenyl)meth-(E)-ylene)-2-oxoindolin-1-yl)methyl)benzoicacid methyl ester

3-Phenyl-propynoic acid phenylamide

Phenylamine (1.86 g, 20 mmol) and phenylpropiolic acid (3.22 g, 22 mmol)were dissolved in dichloromethane (50 ml) and1,3-dicyclohexylcarbodiimide (4.8 g, 23.2 mmol) was added in one portionat 0° C. The mixture was stirred room temperature for 14 h. The mixturewas poured into water and extracted with dichloromethane (3×15 ml). Theorganic layers were combined, dried over anhydrous sodium sulfate andconcentrated in vacuo. Purification by flash column chromatography onsilica gel, eluting with hexanes-EtOAc (6:1 and then 4:1) afforded3-phenyl-propynoic acid phenylamide 2.7 g (62%).

3-{[Phenyl-(3-phenyl-propynoyl)-amino]-methyl}-benzoic acid methyl ester

3-Phenyl-propynoic acid phenylamide (951.4 mg, 4.3 mmol),3-bromomethyl-benzoic acid methyl ester (1.2 g, 5.16 mmol) and Cs₂CO₃(2.1 g, 6.45 mmol) were dissolved in DMF (20 ml). The mixture wasstirred at room temperature for 16 h. The mixture was poured into waterand extracted with ethyl acetate, dried overanhydrous sodium sulfate andconcentrated under reduced pressure. Purification was by flash columnchromatography on silica gel, eluting with hexanes-EtOAc (6:1 and then4:1) afforded 3-{[phenyl-(3-phenyl-propynoyl)-amino]-methyl}-benzoicacid methyl ester 1.03 g (65%).

3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester

To a solution of 3-{[phenyl-(3-phenyl-propynoyl)-amino]-methyl}-benzoicacid methyl ester (369.4 mg, 1 mmol) in THF (5 ml) were addedpalladium(II) acetate (11.2 mg, 0.05 mmol), triphenylphosphine (26.2 mg,0.1 mmol), 1-chloro-4-iodobenzene (262.3 mg, 1.1 mmol) and cesiumfluoride (456 mg, 3 mmol) at room temperature. The solution was stirredfor 3 h at 110° C. under an argon atmosphere. After being quenched withwater, the mixture was extracted with ethyl acetate, dried overmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by flash column chromatography on silica gel eluting with(hexane/ethyl acetate= 5/1) to give3-{3-[1-(4-chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester, yield 297 mg (62%); ¹H NMR (CDCl₃, 300 MHz) δ ppm8.00 (s, 1H), 7.92 (d, 1H), 7.50 (d, 1H), 7.26-7.43 (m, 10H), 7.08 (dt,1H), 6.71 (dt, 1H), 6.59 (d, 1H), 6.52 (d, 1H), 4.95 (s, 2H), 3.90 (s,3H).

Example 63-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-7-fluoro-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester

The title compound was prepared in analogy to Example 5 starting from1-chloro-4-iodo-benzene (commercially available) and3-{[(2-fluoro-phenyl)-(3-phenyl-propynoyl)-amino]-methyl}-benzoic acidmethyl ester. ¹H NMR (300 Hz, CDCl₃): δppm 3.88 (s, 3H), 5.11 (s, 2H),6.22 (d, 1H), 6.61-6.67 (m, 1H), 6.82-6.89 (dd, 1H), 7.26-7.43 (m, 10H),7.52 (d, 1H), 7.92 (d, 1H), 8.01 (s, 1H).

Example 73-(3-Benzhydrylidene-2-oxo-2,3-dihydro-indol-1-ylmethyl)-benzoic acidmethyl ester

The title compound was prepared in analogy to Example 5 starting fromiodo-benzene (commercially available) and 3-{[phenyl-(3-phenylpropynoyl)-amino]-methyl}-benzoic acid methyl ester. ¹H NMR (CDCl₃, 300MHz) δppm 8.01 (s, 1H), 8.00 (d, 1H), 7.93 (d, 1H), 7.33-7.52 (m, 12H),7.05 (dt, 1H), 6.66 (m, 2H), 6.43 (d, 2H), 4.96 (s, 2H), 3.91 (s, 3H).

Example 83-{3-[1-(4-Methoxy-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester

The title compound was prepared in analogy to Example 5 starting from1-iodo 4-methoxy-benzene (commercially available) and3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methylester. ¹H NMR (CDCl₃, 300 MHz) δppm 8.01 (s, 1H), 7.94 (d, 1H), 7.49 (d,1H), 7.26-7.38 (m, 8H), 7.06 (m, 1H), 6.94 (m, 2H), 6.63-6.70 (m, 3H),4.97 (s, 2H), 3.91 (s, 3H), 3.88 (s, 3H).

Example 93-{2-Oxo-3-[1-phenyl-1-p-tolyl-meth-(E)-ylidene]-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester

The title compound was prepared in analogy to Example 5 starting from1-methyl-4-iodo-benzene (commercially available) and3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methylester. ¹H NMR (CDCl₃, 300 MHz) δppm 8.01 (s, 1H), 7.92 (d, 1H),7.24-7.52 (m, 11H), 7.05 (t, 1H), 7.56-7.71 (m, 3H), 4.96 (s, 2H), 3.91(s, 3H), 2.44 (s, 3H).

Example 103-{3-[1-(4-Chloro-phenyl)-1-(2-methoxy-phenyl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester

The title compound was prepared in analogy to Example 5 starting from1-chloro-4-iodo-benzene (commercially available) and3-({[3-(2-methoxy-phenyl)-propynoyl]-phenyl-amino}-methyl)-benzoic acidmethyl ester. ¹H NMR (CDCl₃, 300 MHz) δppm 7.99 (s, 1H), 7.92 (d, 1H),7.26-7.49 (m, 7H), 6.93-7.15 (m, 4H), 6.72 (t, 1H), 6.61-6.64 (m, 2H),4.93 (dd, 2H), 3.90 (s, 3H), 3.63 (s, 3H).

Example 113-{3-[1-(4-Cyano-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester

The title compound was prepared in analogy to Example 5 starting from4-iodo-benzonitrile (commercially available) and 3-{[phenyl-(3-phenylpropynoyl)-amino]-methyl}-benzoic acid methyl ester. ¹H NMR (CDCl₃, 300MHz) δppm 8.00 (s, 1H), 7.93 (d, 1H), 7.74-7.76 (m, 2H), 7.35-7.51 (m,9H), 7.10 (t, 1H), 6.56-6.72 (m, 2H), 6.35 (d, 1H), 4.95 (s, 2H), 3.91(s, 3H)

Example 123-{2-Oxo-3-[1-phenyl-1-(4-trifluoromethyl-phenyl)-meth-(E)-ylidene]-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester

The title compound was prepared in analogy to Example 5 starting from1-iodo-4-trifluoromethyl-benzene (commercially available) and3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methylester. ¹H NMR (300 Hz, CDCl₃) δppm 3.91 (s, 3H), 4.96 (s, 2H), 6.37 (d,1H), 6.67 (dd, 2H), 7.08 (t, 1H), 7.35-7.40 (m, 7H), 7.49 (d, 2H), 7.71(d, 2H), 7.95 (d, 1H), 8.01 (s, 1H).

Example 133-{3-[1-(3-Chloro-4-fluoro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester

The title compound was prepared in analogy to Example 5 starting from2-chloro-1-fluoro-4-iodo-benzene (commercially available) and3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methylester. ¹H NMR (CDCl₃, 300 MHz) δppm 8.00 (s, 1H), 7.93 (d, 1H), 7.50 (d,1H), 7.22-7.42 (m, 9H), 7.09 (dt, 1H), 6.73 (dt, 1H), 6.66 (d, 1H), 6.51(d, 1H), 4.95 (s, 2H), 3.91 (s, 3H).

Example 143-{2-Oxo-3-[1-phenyl-1-(3,4,5-trimethoxy-phenyl)-meth-(E)-ylidene]-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester

The title compound was prepared in analogy to Example 5 starting from5-Iodo-1,2,3-trimethoxy-benzene (commercially available) and3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methylester. ¹H NMR (300 Hz, CDCl₃): δppm 3.76 (s, 6H), 3.91 (s, 3H), 3.94 (s,3H), 4.96 (s, 2H), 6.55 (s, 2H), 6.61-6.71 (m, 4H), 7.06 (t, 1H),7.38-7.40 (m, 5H), 7.53 (d, 1H), 7.91 (d, 1H), 8.02 (s, 1H).

Example 153-{3-[1-(3,4-Difluoro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester

The title compound was prepared in analogy to Example 5 starting from1,2-difluoro-4-iodo-benzene (commercially available) and3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methylester. ¹H NMR (300 Hz, CDCl₃): δppm 3.90 (s, 3H), 4.96 (s, 2H), 6.58 (d,1H), 6.70 (m, 2H), 7.07-7.32 (m, 4H), 7.34-7.43 (m, 6H), 7.50 (d, 1H),7.94 (d, 1H), 8.02 (s, 1H).

Example 163-{3-[1-(3-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester

The title compound was prepared in analogy to Example 5 starting from1-chloro-3-iodo-benzene (commercially available) and3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methylester. ¹H NMR (CDCl₃, 300 MHz) δppm 8.01 (s, 1H), 7.93 (d, 1H), 7.50 (d,1H), 7.26-7.46 (m, 10H), 7.08 (t, 1H), 6.70 (t, 1H), 6.65 (d, 1H), 6.44(d, 1H), 4.96 (s, 2H), 3.90 (s, 3H).

Example 173-{3-[1-(2-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester

The title compound was prepared in analogy to Example 5 starting from1-chloro-2-iodo-benzene (commercially available) and3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methylester. ¹H NMR (CDCl₃, 300 MHz) δppm 8.01 (s, 1H), 7.92 (d, 1H),7.50-7.52 (m, 4H), 7.37-7.42 (m, 7H), 7.07 (t, 1H), 6.62-6.69 (m, 1H),6.05 (d, 1H), 4.96 (dd, 2H), 3.91 (s, 3H).

Example 183-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-5-fluoro-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester

The title compound was prepared in analogy to Example 5 starting from1-chloro-4-iodo-benzene (commercially available) and3-{[(4-fluoro-phenyl)-(3-phenyl-propynoyl)-amino]-methyl}-benzoic acidmethyl ester. ¹H NMR (300 Hz, CDCl₃): δppm 3.91 (s, 3H), 4.94 (s, 2H),6.25 (dd, 1H), 6.54 (dd, 2H), 6.75-6.80 (m, 1H), 7.10 (d, 2H), 7.33-7.54(m, 8H), 7.94 (d, 1H), 7.98 (s, 1H).

Example 193-{3-[1-(3,5-Dichloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester

The title compound was prepared in analogy to Example 5 starting from1,3-dichloro-5-iodobenzene (commercially available) and3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methylester. ¹H NMR (300 Hz, CDCl₃): δppm 3.92 (s, 3H), 4.95 (s, 2H), 6.47 (d,1H), 6.65-6.78 (m, 2H), 7.13 (t, 2H), 7.33-7.43 (m, 8H), 7.52 (d, 1H),7.93 (d, 1H), 8.01 (s, 1H).

Example 203-{3-[1-(2,3-Dichloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester

The title compound was prepared in analogy to Example 5 starting from1,2-dichloro-3-iodobenzene (commercially available) and3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methylester. ¹H NMR (CDCl₃, 300 MHz) δppm 8.00 (s, 1H), 7.92 (d, 1H),7.33-7.54 (m, 9H), 7.23 (dd, 1H), 7.10 (t, 1H), 6.74 (t, 1H), 6.66 (d,1H), 6.55 (d, 1H), 4.95 (s, 2H), 3.90 (s, 3H).

Example 214-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester

The title compound was prepared in analogy to Example 5 starting from1-chloro-4-iodobenzene (commercially available) and 4-{[phenyl-(3-phenylpropynoyl)-amino]-methyl}-benzoic acid methyl ester. ¹H NMR (CDCl₃, 300MHz) δppm 7.97 (d, 1H), 7.25-7.43 (m, 12H), 7.07 (dt, 1H), 6.71 (dt,1H), 6.61 (d, 1H), 6.54 (d, 1H), 4.97 (s, 2H), 3.89 (s, 3H).

Example 223-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-5-methoxy-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester

The title compound was prepared in analogy to Example 5 starting from1-chloro-4-iodobenzene (commercially available) and3-{[(4-methoxy-phenyl)-(3-phenyl-propynoyl)-amino]-methyl}-benzoic acidmethyl ester. ¹H NMR (300 Hz, CDCl₃): δppm 3.49 (s, 3H), 3.91 (s, 3H),4.92 (s, 2H), 6.10 (dd, 1H), 6.51 (d, 1H), 6.62 (dd, 1H), 7.25-7.50 (m,11H), 7.93 (d, 1H), 7.99 (s, 1H).

Example 233-{3-[1-(2-Bromo-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester

The title compound was prepared in analogy to Example 5 starting from1-bromo-2-iodobenzene (commercially available) and 3-{[phenyl-(3-phenylpropynoyl)-amino]-methyl}-benzoic acid methyl ester. ¹H NMR (CDCl₃, 300MHz) δppm 8.01 (s, 1H), 7.93 (d, 1H), 7.71 (d, 1H), 7.30-7.53 (m, 11H),7.04-7.09 (m, 2H), 6.62-7.04 (m, 3H), 6.42 (d, 1H), 6.02 (d, 1H),4.88-5.05 (m, 2H), 3.91 (s, 3H).

Example 243-{3-[1-(2-Chloro-5-trifluoromethyl-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester

The title compound was prepared in analogy to Example 5 starting from1-chloro-2-iodo-4-trifluoromethyl-benzene (commercially available) and3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methylester. ¹H NMR (CDCl₃, 300 MHz) δppm 8.01 (s, 1H), 7.93 (d, 1H),7.63-7.67 (m, 2H), 7.33-7.52 (m, 7H), 7.10 (t, 1H), 6.64-6.71 (m, 2H),5.98 (d, 1H), 4.87-5.04 (m, 2H), 3.91 (s, 3H).

Example 253-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-4-fluoro-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester

The title compound was prepared in analogy to Example 5 starting from1-chloro-4-iodo-benzene (commercially available) and3-{[(3-fluoro-phenyl)-(3-phenyl-propynoyl)-amino]-methyl}-benzoic acidmethyl ester. ¹H NMR (300 Hz, CDCl₃): δppm 4.97 (s, 2H), 6.39-6.51 (m,2H), 7.25-7.45 (m, 11H), 7.53 (d, 1H), 7.99 (d, 1H), 8.00 (s, 1H).

Example 263-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-6-fluoro-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester

The title compound was prepared in analogy to Example 5 starting from1-chloro-4-iodo-benzene (commercially available) and3-{[(3-fluoro-phenyl)-(3-phenyl-propynoyl)-amino]-methyl}-benzoic acidmethyl ester. ¹H NMR (300 Hz, CDCl₃): δppm 3.90 (s, 3H), 4.96 (s, 2H),6.48 (d, 1H), 7.10 (d, 1H), 7.19 (d, 1H), 7.31-7.50 (m, 11H), 7.94 (d,1H), 7.98 (s, 1H).

Example 273-{3-[1-(3-Bromo-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester

The title compound was prepared in analogy to Example 5 starting from1-bromo-3-iodobenzene (commercially available) and 3-{[phenyl-(3-phenylpropynoyl)-amino]-methyl}-benzoic acid methyl ester. ¹H NMR (CDCl₃, 300MHz) δppm 8.01 (s, 1H), 7.93 (d, 1H), 7.31-7.61 (m, 11H), 7.08 (t, 1H),6.64-6.73 (m, 2H), 6.44 (d, 1H), 4.95 (s, 2H), 3.91 (s, 3H).

Example 283-{3-[1-(2-Methylsulfanyl-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester

The title compound was prepared in analogy to Example 5 starting from1-iodo-2-methylsulfanyl-benzene (commercially available) and3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methylester. ¹H NMR (300 Hz, CDCl₃): δppm 2.31 (s, 3H), 3.90 (s, 3H), 5.00(dd, 2H), 6.03 (d, 1H), 6.60-6.64 (m, 2H), 7.04 (t, 1H), 7.26-7.30 (m,2H), 7.33-7.56 (m, 9H), 7.95 (d, 1H), 8.01 (s, 1H).

Example 293-{7-Chloro-3-[1-(4-chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-5-fluoro-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester

The title compound was prepared in analogy to Example 5 starting from1-chloro-4-iodo-benzene (commercially available) and3-{[(2-chloro-4-fluoro-phenyl)-(3-phenyl-propynoyl)-amino]-methyl}-benzoicacid methyl ester. ¹H NMR (300 Hz, CDCl₃): δppm 3.90 (s, 3H), 5.38 (s,2H), 6.01 (dd, 1H), 6.80 (dd, 1H), 7.27-7.40 (m, 9H), 7.45-7.50 (m, 3H),7.92 (m, 2H).

Example 303-{2-Oxo-3-[1-phenyl-1-(3-trifluoromethyl-phenyl)-meth-(E)-ylidene]-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester

The title compound was prepared in analogy to Example 5 starting from1-iodo-3-trifluoromethyl-benzene (commercially available) and3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methylester. ¹H NMR (CDCl₃, 300 MHz) δppm 8.01 (s, 1H), 7.95 (d, 1H), 7.72 (d,1H), 7.50-7.63 (m, 3H), 7.36-7.42 (m, 4H), 7.08 (t, 1H), 6.64-6.68 (m,2H), 6.42 (d, 1H), 4.96 (s, 2H), 3.91 (s, 3H).

Example 313-{2-Oxo-3-[1-phenyl-1-(4-sulfamoyl-phenyl)-meth-(E)-ylidene]-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester

The title compound was prepared in analogy to Example 5 starting from4-iodo-benzenesulfonamide (commercially available) and3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methylester. ¹H NMR (300 Hz, CDCl₃): δppm 3.90 (s, 3H), 4.95 (s, 2H), 5.02 (s,2H), 6.41 (d, 1H), 6.65-6.71 (m, 2H), 7.09 (t, 1H), 7.26-7.33 (m, 2H),7.35-7.42 (m, 6H), 7.58-7.60 (m, 3H), 7.99 (d, 1H), 8.07 (s, 1H).

Example 323-{3-[1-(2-Methanesulfonyl-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester

The title compound was prepared in analogy to Example 5 starting from1-iodo-2-methanesulfonyl-benzene (commercially available) and3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methylester. ¹H NMR (300 Hz, CDCl₃): δppm 1.89 (s, 1.5H), 2.50 (s, 1.5H), 3.90(s, 3H), 4.98 (dd, 2H), 5.98 (dd, 1H), 6.65-6.68 (m, 2H), 7.07 (m, 1H),7.35-7.58 (m, 8H), 7.61 (t, 1H), 7.78 (t, 1H), 7.99 (d, 1H), 8.02 (d,1H), 8.20 (d, 1H).

Example 333-{2-Oxo-3-[1-phenyl-1-thiophen-3-yl-meth-(E)-ylidene]-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester

The title compound was prepared in analogy to Example 5 starting from3-iodo-thiophene (commercially available) and 3-{[phenyl-(3-phenylpropynoyl)-amino]-methyl}-benzoic acid methyl ester. ¹H NMR (300 Hz,CDCl₃): δppm 3.91 (s, 3H), 4.96 (s, 2H), 6.65 (d, 1H), 6.76-6.82 (m,2H), 7.06-7.11 (m, 2H), 7.33-7.43 (m, 8H), 7.50 (d, 1H), 7.92 (d, 1H),8.01 (s, 1H).

Example 343-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester

The title compound was prepared in analogy to Example 5 starting from1-chloro-4-iodo-benzene (commercially available) and3-{[phenyl-(3-phenyl-propynoyl)-amino]-methyl}-benzoic acid methylester. ¹H NMR (300 Hz, CDCl₃): δppm 3.91 (s, 3H), 4.96 (s, 2H), 6.42 (d,1H), 6.63-6.66 (m, 2H), 7.06 (t, 1H), 7.33-7.52 (m, 11H), 7.92 (d, 1H),8.01 (s, 1H).

Example 353-{3-[1-(4-Chloro-phenyl)-1-(4-trifluoromethyl-phenyl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester

The title compound was prepared in analogy to Example 5 starting from1-iodo-4-trifluoromethyl-benzene (commercially available) and3-({[3-(4-chloro-phenyl)-propynoyl]-phenyl-amino}-methyl)-benzoic acidmethyl ester. ¹H NMR (300 Hz, CDCl₃): δppm 3.91 (s, 3H), 4.96 (s, 2H),6.37 (d, 1H), 6.66-6.71 (m, 2H), 7.08 (t, 1H), 7.26-7.52 (m, 9H), 7.73(d, 2H), 7.94 (d, 1H), 8.01 (s, 1H).

Example 36(4-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-phenoxy)-aceticacid ethyl ester

The title compound was prepared in analogy to Example 5 starting from1-chloro-4-iodo-benzene (commercially available) and(4-{[phenyl-(3-phenyl-propynoyl)-amino]-methyl}-phenoxy)-acetic acidethyl ester. ¹H NMR (300 Hz, CDCl₃): δppm 1.28 (t, 3H), 4.26 (q, 2H),4.57 (s, 2H), 4.84 (s, 2H), 6.51 (d, 1H), 6.67-6.71 (m, 2H), 6.83 (d,2H), 7.08 (t, 1H), 7.24-7.42 (m, 11H).

Example 373-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-N-isopropyl-benzamide

The title compound was prepared in analogy to Example 5 starting from1-chloro-4-iodo-benzene (commercially available) andN-isopropyl-3-{[phenyl-(3-phenyl-propynoyl)-amino]-methyl}-benzamide. ¹HNMR (CDCl₃, 300 MHz) δppm 7.74 (s, 1H), 7.60 (d, 1H), 7.26-7.43 (m,10H), 7.07 (dt, 2H), 6.70 (t, 1H), 6.68 (d, 1H), 6.53 (d, 1H), 5.99 (d,1H), 4.94 (s, 2H), 4.26 (m, 1H), 1.26 (s, 3H), 1.24 (s, 3H).

Example 386-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-nicotinicacid methyl ester

The title compound was prepared in analogy to Example 5 starting from1-chloro-4-iodo-benzene (commercially available) and6-{[phenyl-(3-phenyl-propynoyl)-amino]-methyl}-nicotinic acid methylester. ¹H NMR (300 Hz, CDCl₃): δppm 3.93 (s, 3H), 5.10 (s, 2H), 6.54 (d,1H), 6.57-6.75 (m, 2H), 7.08 (t, 1H), 7.28-7.44 (m, 10H), 8.20 (d, 1H),9.16 (s, 1H).

Example 392-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-thiazole-4-carboxylicacid ethyl ester

The title compound was prepared in analogy to Example 5 starting from1-chloro-4-iodo-benzene (commercially available) and2-{[phenyl-(3-phenyl-propynoyl)-amino]-methyl}-thiazole-4-carboxylicacid ethyl ester. ¹H NMR (300 Hz, CDCl₃): δppm 1.39 (t, 3H), 4.44 (q,2H), 5.27 (s, 2H), 6.58 (d, 1H), 6.78 (t, 1H), 6.88 (d, 1H), 7.13 (t,1H), 7.31-7.43 (m, 9H), 8.10 (s, 1H).

Example 403-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-1-(4-methoxy-benzyl)-1,3-dihydro-indol-2-one

The title compound was prepared in analogy to Example 5 starting from1-chloro-4-iodo-benzene (commercially available) and 3-phenyl-propynoicacid (4-methoxy-benzyl)-phenyl-amide. ¹H NMR (300 Hz, CDCl₃): δppm 3.77(s, 3H), 4.88 (s, 2H), 6.53 (d, 1H), 6.67-6.71 (m, 2H), 6.80 (dd, 1H),6.85-6.90 (m, 2H), 7.07 (t, 1H), 7.19-7.43 (m, 10H).

Example 413-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-1-(3,4,5-trihydroxy-benzyl)-1,3-dihydro-indol-2-one;and Example 423-[1-(4-Chloro-phenyl)-1-phenyl-meth-(Z)-ylidene]-1-(3,4,5-trihydroxy-benzyl)-1,3-dihydro-indol-2-one

3-Phenyl-propynoic acid phenyl-(3,4,5-trimethoxy-benzyl)-amide

3-Phenyl-propynoic acid phenylamide (951.4 mg, 4.3 mmol),5-bromomethyl-1,2,3-trimethoxy-benzene (1.35 g, 5.16 mmol), and Cs₂CO₃(2.1 g, 6.45 mmol) were dissolved in DMF (20 ml). The mixture wasstirred at room temperature for 16 h. The mixture was poured into waterand extracted with ethyl acetate, dried overanhydrous sodium sulfate andconcentrated under reduced pressure. Purification was by flash columnchromatography on silica gel, eluting with hexanes-EtOAc (6:1 and then4:1) afforded 3-phenyl-propynoic acidphenyl-(3,4,5-trimethoxy-benzyl)-amide 1.03 g (65%).

3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-1-(3,4,5-trimethoxy-benzyl)-1,3-dihydro-indol-2-oneand3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(Z)-ylidene]-1-(3,4,5-trimethoxy-benzyl)-1,3-dihydro-indol-2-one

To a solution of 3-phenyl-propynoic acidphenyl-(3,4,5-trimethoxy-benzyl)-amide (401.5 mg, 1 mmol) in THF (5 ml)were added palladium(II) acetate (11.2 mg, 0.05 mmol),triphenylphosphine (26.2 mg, 0.1 mmol), 1-chloro-4-iodobenzene (262.3mg, 1.1 mmol) and cesium fluoride (456 mg, 3 mmol) at room temperature.The solution was stirred for 3 h at 110° C. under an argon atmosphere.After being quenched with water, the mixture was extracted with ethylacetate, dried over magnesium sulfate and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel eluting with (hexane/ethyl acetate= 5/1) to give a mixture of3-[1-(4-chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-1-(3,4,5-trimethoxy-benzyl)-1,3-dihydro-indol-2-oneand3-[1-(4-chloro-phenyl)-1-phenyl-meth-(Z)-ylidene]-1-(3,4,5-trimethoxy-benzyl)-1,3-dihydro-indol-2-one,yield 317 mg (62%);

3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-1-(3,4,5-trihydroxy-benzyl)-1,3-dihydro-indol-2-oneand3-[1-(4-chloro-phenyl)-1-phenyl-meth-(Z)-ylidene]-1-(3,4,5-trihydroxy-benzyl)-1,3-dihydro-indol-2-one

To a solution of3-[1-(4-chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-1-(3,4,5-trimethoxy-benzyl)-1,3-dihydro-indol-2-oneand3-[1-(4-chloro-phenyl)-1-phenyl-meth-(Z)-ylidene]-1-(3,4,5-trimethoxy-benzyl)-1,3-dihydro-indol-2-one(317 mg, 0.62 mmol) in dichloromethane (5 ml) was added a solution ofboron tribromide (1M in CH₂Cl₂, 3 ml) at room temperature. The mixturewas stirred at room temperature for 5 h. After being quenched by pouringinto ice water, the mixture was extracted with ethyl acetate, dried overmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by flash column chromatography on silica gel eluting with(hexane/ethyl acetate= 1/1) to give3-[1-(4-chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-1-(3,4,5-trihydroxy-benzyl)-1,3-dihydro-indol-2-one(60 mg). ¹H NMR (300 Hz, CDCl₃): δppm 4.66 (s, 2H), 5.60 (b, 1H), 6.31(s, 2H), 6.56 (d, 1H), 6.67-6.82 (m, 2H), 7.00-7.23 (m, 8H), 7.38 (d,2H); and3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(Z)-ylidene]-1-(3,4,5-trihydroxy-benzyl)-1,3-dihydro-indol-2-one(40 mg). ¹H NMR (300 Hz, CDCl₃): δppm 4.72 (s, 2H), 5.33 (b, 1H), 6.05(b, 1H), 6.40 (s, 2H), 6.44 (d, 1H), 6.67 (t, 1H), 6.82 (d, 1H), 7.00(d, 2H), 7.10-7.15 (m, 3H), 7.23-7.26 (m, 2H), 7.37-7.46 (m, 3H).

Example 433-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-1-(4-hydroxy-benzyl)-1,3-dihydro-indol-2-one

The title compound was prepared in analogy to Example 41 starting from3-[1-(4-chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-1-(4-methoxy-benzyl)-1,3-dihydro-indol-2-one.¹H NMR (300 Hz, CDCl₃): δppm 4.81 (s, 2H), 6.51 (d, 1H), 6.53-6.74 (m,4H), 7.08-7.11 (m, 3H), 7.24-7.42 (m, 9H).

Example 443-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid

3-{3-[1-(4-chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester (94 mg, 0.2 mmol) was dissolved in THF (2 ml) andwater (2 ml) and LiOH.H₂O (42 mg, 1 mmol) was added in one portion. Themixture was stirred at 50° C. for 16 h. The mixture was concentratedunder reduced pressure, and acidified to pH=3. Purification bypreparative HPLC afforded3-((3-((4-chlorophenyl)(phenyl)meth-(E)-ylene)-2-oxoindolin-1-yl)methyl)benzoicacid as light yellow powder. Yield 30 mg (70%). ¹H NMR (CDCl₃, 300 MHz)δppm 8.06 (s, 1H), 7.99 (d, 1H), 7.55 (d, 1H), 7.29-7.43 (m, 10H), 7.09(t, 1H), 6.74-6.65 (m, 2H), 6.55 (d, 1H),

Example 453-{3-[1-(4-Fluoro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid

The title compound was prepared in analogy to Example 44 starting from3-{3-[1-(4-fluoro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester. ¹H NMR (CDCl₃, 300 MHz) δppm 8.07 (s, 1H), 8.00 (d,1H), 7.56 (d, 1H), 7.33-7.48 (m, 8H), 7.07-7.17 (m, 3H), 6.66-6.74 (m,2H), 6.52 (d, 1H), 4.99 (s, 2H).

Example 463-{3-[1-(4-Methoxy-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid

The title compound was prepared in analogy to Example 44 starting from3-{3-[1-(4-methoxy-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester. ¹H NMR (CDCl₃, 300 MHz) δppm 8.07 (s, 1H), 8.00 (d,1H), 7.55 (d, 1H), 7.26-7.38 (m, 8H), 7.07 (m, 1H), 6.94 (m, 2H),6.65-6.71 (m, 3H), 4.98 (s, 2H), 3.88 (s, 3H).

Example 473-{3-[1-(4-Chloro-phenyl)-1-(2-methoxy-phenyl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid

The title compound was prepared in analogy to Example 44 starting from3-{3-[1-(4-chloro-phenyl)-1-(2-methoxy-phenyl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1ylmethyl}-benzoic acid methyl ester. ¹H NMR (CDCl₃, 300 MHz) δppm 8.04(s, 1H), 7.99 (d, 1H), 7.54 (d, 1H), 7.32-7.44 (m, 6H), 7.07-7.15 (m,2H), 6.93-7.01 (m, 2H), 6.73 (t, 1H), 6.64 (t, 2H), 4.95 (dd, 2H), 3.90(s, 3H), 3.72 (s, 3H).

Example 483-{2-Oxo-3-[1-phenyl-1-(4-trifluoromethyl-phenyl)-meth-(E)-ylidene]-2,3-dihydro-indol-1-ylmethyl}-benzoicacid

The title compound was prepared in analogy to Example 44 starting from3-{2-oxo-3-[1-phenyl-1-(4-trifluoromethyl-phenyl)-meth-(E)-ylidene]-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester. ¹H NMR (300 Hz, CDCl₃): δppm 4.98 (s, 2H), 6.40 (d,1H), 6.68 (dd, 2H), 7.10 (t, 1H), 7.35-7.55 (m, 9H), 7.71 (d, 2H), 7.99(d, 1H), 8.07 (s, 1H).

Example 493-{2-Oxo-3-[1-phenyl-1-(2-trifluoromethoxy-phenyl)-meth-(E)-ylidene]-2,3-dihydro-indol-1-ylmethyl}-benzoicacid

The title compound was prepared in analogy to Example 44 starting from3-{2-oxo-3-[1-phenyl-1-(2-trifluoromethoxy-phenyl)-meth-(E)-ylidene]-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester. ¹H NMR (300 Hz, CDCl₃): δppm 3.91 (s, 3H,), 5.96 (s,2H), 6.37 (d, 1H), 6.64-6.72 (m, 2H), 7.07 (dt, 1H), 7.51-7.33 (m, H),7.70 (d, 2H) 7.93 (d, 1H), 8.01 (s, 1H).

Example 503-{3-[1-(3-Chloro-4-fluoro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid

The title compound was prepared in analogy to Example 44 starting from3-{3-[1-(3-chloro-4-fluoro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester. ¹H NMR (CDCl₃, 300 MHz) δppm 8.07 (s, 1H), 8.01 (d,1H), 7.56 (d, 1H), 7.34-7.45 (m, 6H), 7.22-7.28 (m, 3H), 7.11 (dt, 1H),6.74 (dt, 1H), 6.68 (d, 1H), 6.53 (d, 1H), 4.98 (s, 2H).

Example 513-{2-Oxo-3-[1-phenyl-1-(3,4,5-trimethoxy-phenyl)-meth-(E)-ylidene]-2,3-dihydro-indol-1-ylmethyl}-benzoicacid

The title compound was prepared in analogy to Example 44 starting from3-{2-oxo-3-[1-phenyl-1-(3,4,5-trimethoxy-phenyl)-meth-(E)-ylidene]-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester. ¹H NMR (300 Hz, CDCl₃): δppm 3.79 (s, 6H), 3.94 (s,3H), 4.98 (s, 2H), 6.55 (s, 2H), 6.61-6.72 (m, 4H), 7.08 (t, 1H),7.40-7.45 (m, 5H), 7.58 (d, 1H), 7.99 (d, 1H), 8.07 (s, 1H).

Example 523-{3-[1-(3-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid

The title compound was prepared in analogy to Example 44 starting from3-{3-[1-(3-chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester. ¹H NMR (CDCl₃, 300 MHz) δppm 8.07 (s, 1H), 7.90 (d,1H), 7.56 (d, 1H), 7.26-7.50 (m, 10H), 7.09 (t, 1H), 6.66-6.70 (m, 2H),6.45 (d, 1H), 4.98 (s, 2H).

Example 533-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-5-fluoro-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid

The title compound was prepared in analogy to Example 44 starting from3-{3-[1-(4-chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-5-fluoro-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester. ¹H NMR (300 Hz, CDCl₃): δppm 4.97 (s, 2H), 6.26 (dd,1H), 6.55 (dd, 2H), 6.77-6.80 (m, 1H), 7.10 (d, 2H), 7.33-7.48 (m, 7H),7.53 (d, 2H), 8.01 (d, 1H), 8.04 (s, 1H).

Example 543-{3-[1-(3,5-Dichloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid

The title compound was prepared in analogy to Example 44 starting from3-{3-[1-(3,5-dichloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester. ¹H NMR (300 Hz, CDCl₃): δppm 4.96 (s, 2H), 6.48 (d,1H), 6.65-6.78 (m, 2H), 7.13 (t, 2H), 7.33-7.43 (m, 8H), 7.56 (d, 1H),7.98 (d, 1H), 8.08 (s, 1H).

Example 553-{3-[1-(2,3-Dichloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid

The title compound was prepared in analogy to Example 44 starting from3-{3-[1-(2,3-dichloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester. ¹H NMR (CDCl₃, 300 MHz) δppm 8.07 (s, 1H), 8.01 (d,1H), 7.33-7.57 (m, 9H), 7.22-7.26 (m, 1H), 7.12 (t, 1H), 6.75 (t, 1H),6.68 (d, 1H), 6.56 (d, 1H), 4.97 (s, 2H).

Example 562-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid

The title compound was prepared in analogy to Example 44 starting from2-{3-[1-(4-chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester. ¹H NMR (CDCl₃, 300 MHz) δppm 8.10 (d, 1H), 7.32-7.48(m, 11H), 7.18 (d, 1H), 7.11 (t, 1H), 6.75 (t, 1H), 6.65 (d, 1H), 6.58(d, 1H), 5.39 (s, 2H).

Example 574-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid

The title compound was prepared in analogy to Example 44 starting from4-{3-[1-(4-chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester. ¹H NMR (CDCl₃, 300 MHz) δppm 8.05 (d, 2H), 7.29-7.44(m, 11H), 7.09 (t, 1H), 6.72 (t, 1H), 7.29 (d, 1H), 6.59 (d, 1H), 4.98(s, 2H), 3.89 (s, 3H).

Example 583-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-5-methoxy-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid

The title compound was prepared in analogy to Example 44 starting from3-{3-[1-(4-chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-5-methoxy-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester. ¹H NMR (300 Hz, CDCl₃): δppm 3.49 (s, 3H), 4.95 (s,2H), 6.10 (dd, 1H), 6.51 (d, 1H), 6.64 (dd, 1H), 7.25-7.45 (m, 10H),7.54 (d, 1H), 8.00 (d, 1H), 8.05 (s, 1H).

Example 596-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-nicotinicacid

The title compound was prepared in analogy to Example 44 starting from6-{3-[1-(4-chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-nicotinicacid methyl ester. ¹H NMR (300 Hz, CDCl₃): δppm 5.19 (s, 2H), 6.56 (d,1H), 6.58-6.77 (m, 2H), 7.09 (t, 1H), 7.28-7.44 (m, 10H), 8.30 (d, 1H),9.26 (s, 1H).

Example 603-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-4-fluoro-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid

The title compound was prepared in analogy to Example 44 starting from3-{3-[1-(4-chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-4-fluoro-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester. ¹H NMR (300 Hz, CDCl₃): δppm 4.97 (s, 2H), 6.39-6.51(m, 2H), 7.25-7.45 (m, 11H), 7.53 (d, 1H), 7.99 (d, 1H), 8.00 (s, 1H).

Example 613-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-6-fluoro-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid

The title compound was prepared in analogy to Example 44 starting from3-{3-[1-(4-chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-6-fluoro-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester. ¹H NMR (300 Hz, CDCl₃): δppm 4.88 (s, 2H), 6.40-6.429(m, 1H), 7.08-7.10 (m, 1H), 7.20 (d, 1H), 7.31-7.38 (m, 10H), 7.42 (d,1H), 7.90 (d, 1H), 7.94 (s, 1H).

Example 623-{3-[1-(2-Methylsulfanyl-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid

The title compound was prepared in analogy to Example 44 starting from3-{3-[1-(2-methylsulfanyl-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester. ¹H NMR (300 Hz, CDCl₃): δppm 2.31 (s, 3H), 5.00 (dd,2H), 6.04 (d, 1H), 6.63-6.64 (m, 2H), 7.07 (t, 1H), 7.26-7.30 (m, 2H),7.33-7.46 (m, 6H), 7.58-7.60 (m, 2H), 7.99 (d, 1H), 8.07 (s, 1H).

Example 633-{2-Oxo-3-[1-phenyl-1-pyridin-3-yl-meth-(E)-ylidene]-2,3-dihydro-indol-1-ylmethyl}-benzoicacid

The title compound was prepared in analogy to Example 44 starting from3-{2-oxo-3-[1-phenyl-1-pyridin-3-yl-meth-(E)-ylidene]-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester. ¹H NMR (300 Hz, CDCl₃): δppm 4.98 (s, 2H), 6.40 (d,1H), 6.65-6.68 (m, 2H), 7.07 (t, 1H), 7.35-7.42 (m, 8H), 7.58 (d, 2H),7.69 (d, 1H), 7.99 (d, 1H), 8.04 (s, 1H).

Example 643-{3-[1-(2-Chloro-5-trifluoromethyl-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid

The title compound was prepared in analogy to Example 44 starting from3-{3-[1-(2-chloro-5-trifluoromethyl-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester. ¹H NMR (CDCl₃, 300 MHz) δppm 8.06 (s, 1H), 8.00 (d,1H), 7.40-7.67 (m, 10H), 7.11 (t, 1H), 6.66-6.72 (m, 2H), 5.98 (d, 1H),4.89-5.06 (m, 2H), 3.91 (s, 3H).

Example 653-{3-[1-(3,5-Bis-trifluoromethyl-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid

The title compound was prepared in analogy to Example 44 starting from3-{3-[1-(3,5-bis-trifluoromethyl-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester. ¹H NMR (CDCl₃, 300 MHz) δppm 8.24 (s, 1H), 7.95-8.10(m, 4H), 7.78-7.87 (m, 3H), 7.67 (d, 2H), 7.29-7.58 (m, 6H), 7.21 (t,1H), 6.68-6.71 (m, 2H), 6.27 (d, 1H), 4.98 (s, 2H), 3.91 (s, 3H).

Example 663-{2-Oxo-3-[1-phenyl-1-(3-trifluoromethyl-phenyl)-meth-(E)-ylidene]-2,3-dihydro-indol-1-ylmethyl}-benzoicacid

The title compound was prepared in analogy to Example 44 starting from3-{2-oxo-3-[1-phenyl-1-(3-trifluoromethyl-phenyl)-meth-(E)-ylidene]-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester. ¹H NMR (CDCl₃, 300 MHz) δppm 8.08 (s, 1H), 8.01 (d,1H), 7.72 (d, 1H), 7.64-7.56 (m, 4H), 7.35-7.54 (m, 4H), 7.10 (dt, 1H),6.66-6.70 (m, 2H), 6.33 (dd, 1H), 4.98 (s, 2H).

Example 673-{2-Oxo-3-[1-phenyl-1-(4-sulfamoyl-phenyl)-meth-(E)-ylidene]-2,3-dihydro-indol-1-ylmethyl}-benzoicacid

The title compound was prepared in analogy to Example 44 starting from3-{2-oxo-3-[1-phenyl-1-(4-sulfamoyl-phenyl)-meth-(E)-ylidene]-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester. ¹H NMR (300 Hz, CDCl₃): δppm 4.97 (s, 2H), 5.17 (s,2H), 6.42 (d, 1H), 6.64-6.71 (m, 2H), 7.08 (t, 1H), 7.26-7.60 (m, 11H),7.97 (s, 1H), 8.00 (s, 1H).

Example 683-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid

The title compound was prepared in analogy to Example 44 starting from3-{3-[1-(4-chloro-phenyl)-1-phenyl-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester. ¹H NMR (300 Hz, CDCl₃): δppm 4.96 (s, 2H), 6.42 (d,1H), 6.63-6.66 (m, 2H), 7.06 (t, 1H), 7.33-7.52 (m, 11H), 7.92 (d, 1H),8.01 (s, 1H).

Example 693-{3-[1-(4-Chloro-phenyl)-1-(4-trifluoromethyl-phenyl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid

The title compound was prepared in analogy to Example 44 starting from3-{3-[1-(4-chloro-phenyl)-1-(4-trifluoromethyl-phenyl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester. ¹H NMR (300 Hz, CDCl₃): δppm 4.98 (s, 2H), 6.38 (d,1H), 6.68-6.73 (m, 2H), 7.08 (t, 1H), 7.26-7.52 (m, 9H), 7.72 (d, 2H),8.01 (d, 1H), 8.08 (s, 1H).

Example 70(4-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-phenoxy)-aceticacid

The title compound was prepared in analogy to Example 44 starting from(4-{3-[1-(4-chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-phenoxy)-aceticacid methyl ester. ¹H NMR (300 Hz, CDCl₃): δppm 4.56 (s, 2H), 4.85 (s,2H), 6.51 (d, 1H), 6.53-6.73 (m, 2H), 6.83 (d, 2H), 7.08 (t, 1H),7.24-7.42 (m, 11H).

Example 713-{3-[1-(4-Isopropyl-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid

The title compound was prepared in analogy to Example 44 starting from3-{3-[1-(4-isopropyl-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester. ¹H NMR (300 Hz, CDCl₃): δppm 1.31 (d, 6H), 2.94-3.01(m, 1H), 4.99 (s, 2H), 6.56 (d, 1H), 6.67 (dd, 2H), 7.08 (t, 1H), 7.27(s, 4H), 7.38-7.42 (m, 6H), 7.51 (d, 1H), 7.99 (d, 1H), 8.08 (s, 1H)

Example 723-{3-[1-(3,4-Difluoro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid

The title compound was prepared in analogy to Example 44 starting from3-{3-[1-(3,4-difluoro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester. ¹H NMR (300 Hz, CDCl₃): δppm 4.97 (s, 2H), 6.51 (d,1H), 6.71 (m, 2H), 7.08-7.26 (m, 4H), 7.34-7.43 (m, 6H), 7.56 (d, 1H),8.00 (d, 1H), 8.05 (s, 1H).

Example 733-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-7-fluoro-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid

The title compound was prepared in analogy to Example 44 starting from3-{3-[1-(4-chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-7-fluoro-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester. ¹H NMR (300 Hz, CDCl₃): δppm 5.13 (s, 2H), 6.32 (d,1H), 6.63-6.67 (m, 1H), 6.82-6.89 (dd, 1H), 7.26-7.43 (m, 10H), 7.59 (d,1H), 7.99 (d, 1H), 8.08 (s, 1H).

Example 743-{5-Chloro-3-[1-(4-chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid

The title compound was prepared in analogy to Example 44 starting from3-{5-chloro-3-[1-(4-chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester. ¹H NMR (300 Hz, CDCl₃): δppm 4.97 (s, 2H), 6.58 (m,2H), 7.05 (dd, 1H), 7.20 (m, 1H), 7.27-7.46 (m, 9H), 7.52 (d, 1H), 8.01(d, 1H), 8.04 (s, 1H).

Example 753-{3-[1-(2-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid

The title compound was prepared in analogy to Example 44 starting from3-{3-[1-(2-chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester. ¹H NMR (CDCl₃, 300 MHz) δppm 8.06 (s, 1H), 7.99 (d,1H), 7.50-7.57 (m, 3H), 7.37-7.44 (m, 7H), 7.07 (t, 1H), 6.63-6.70 (m,2H), 6.05 (d, 1H), 4.97 (dd, 2H).

Example 762-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-thiazole-4-carboxylicacid

The title compound was prepared in analogy to Example 44 starting from2-{3-[1-(4-chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-thiazole-4-carboxylicacid methyl ester. ¹H NMR (300 Hz, CDCl₃): δppm 5.27 (s, 2H), 6.59 (d,1H), 6.78 (t, 1H), 6.87 (d, 1H), 7.15 (t, 1H), 7.31-7.43 (m, 9H), 8.22(s, 1H).

Example 773-[3-(4-Methyl-1-phenyl-pent-(Z)-ylidene)-2-oxo-2,3-dihydro-indol-1-ylmethyl]-benzoicacid methyl ester

To a degassed refluxing solution of3-{[(2-iodo-phenyl)-(3-phenyl-propynoyl)-amino]-methyl}-benzoic acidmethyl ester (100 mg, 0.2 mmol) and Ni(PPh₃)₂I₂ (16 mg, 0.02 mmol) inCH₂Cl₂ (8 ml) was added 3-methylbutylzinc bromide (151 mg, 0.7 mmol) inCH₂Cl₂ (1 ml). The reaction was stirred at 40° C. for 6 h and then thesolution was cooled to room temperature. The resultant solution wasdiluted with ethyl acetate (50 ml). The organic layer was washed withaqueous HCl solution (4%, 10 ml), brine (3×10 ml). The aqueous layer wasback-extracted with ethyl acetate (3×10 ml). The combined organic layerwas dried over anhydrous sodium sulfate. After filtration, the solventwas removed under reduced pressure and the residue was purified bycolumn chromatography on silica gel, eluting with petrol ether-ethylacetate, to give3-{3-[4-methyl-1-phenyl-pent-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester (24 mg, 28%) as light yellow solid. ¹H NMR (300 Hz,CDCl₃): δppm 0.88 (d, 6H), 1.43-1.55 (m, 2H), 1.68-1.72 (m, 1H),2.93-2.99 (m, 2H), 3.91 (s, 3H), 4.89 (s, 2H), 6.64 (d, 1H), 7.05 (t,1H), 7.15 (t, 1H), 7.28-7.38 (m, 4H), 7.40-7.47 (m, 3H), 7.62 (d, 1H),7.91 (d, 1H), 7.95 (s, 1H); and3-{3-[4-methyl-1-phenyl-pent-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester (29 mg, 33%) as light yellow solid. ¹H NMR (300 Hz,CDCl₃): δppm 0.88 (d, 6H), 1.36-1.44 (m, 2H), 1.64-1.68 (m, 1H),3.33-3.38 (m, 2H), 3.91 (s, 3H), 5.04 (s, 2H), 6.01 (d, 1H), 6.58-6.61(m, 2H), 6.96-7.02 (t, 1H), 7.26-7.29 (m, 2H), 7.37 (t, 2H), 7.43-7.52(m, 3H), 7.93 (d, 1H), 8.03 (s, 1H).

Example 783-{3-[3,3-Dimethyl-1-phenyl-but-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester

The title compound was prepared in analogy to Example 77 starting fromtert-butylzinc bromide (commercially available) and3-{[(2-iodo-phenyl)-(3-phenyl-propynoyl)-amino]-methyl}-benzoic acidmethyl ester. ¹H NMR (300 Hz, CDCl₃): δppm 0.80 (s, 9H), 2.74 (s, 2H),3.90 (s, 3H), 5.67 (s, 2H), 6.98 (t, 1H), 7.12-7.52 (m, 10H), 7.93 (d,1H), 8.03 (s, 1H).

Example 793-{3-[2-(4-Chloro-phenyl)-1-phenyl-eth-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester

The title compound was prepared in analogy to Example 77 starting from4-chloro-benzylzinc bromide (commercially available) and3-{[(2-iodo-phenyl)-(3-phenyl-propynoyl)-amino]-methyl}-benzoic acidmethyl ester. ¹H NMR (300 Hz, CDCl₃): δppm 3.92 (s, 3H), 4.73 (s, 2H),5.07 (s, 2H), 5.99 (d, 1H), 6.58-6.65 (m, 2H), 7.08-7.20 (m, 7H),7.37-7.43 (m, 4H), 7.52 (d, 1H), 7.93 (d, 1H), 8.06 (s, 1H).

Example 803-{3-[3,3-Dimethyl-1-phenyl-but-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester

The title compound was prepared in analogy to Example 77 starting fromtert-butylzinc bromide (commercially available) and3-{[(2-iodo-phenyl)-(3-phenyl-propynoyl)-amino]-methyl}-benzoic acidmethyl ester. ¹H NMR (300 Hz, CDCl₃): δppm 0.91 (s, 9H), 3.48 (s, 2H),3.90 (s, 3H), 5.03 (s, 2H), 6.22 (d, 1H), 6.56-6.62 (m, 2H), 6.98 (t,1H), 7.36-7.50 (m, 7H), 7.92 (d, 1H), 8.02 (s, 1H).

Example 813-[3-(4-Methyl-1-phenyl-pent-(Z)-ylidene)-2-oxo-2,3-dihydro-indol-1-ylmethyl]-benzoicacid

3-{3-[4-Methyl-1-phenyl-pent-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester (24 mg, 0.05 mmol) was dissolved in THF (1 ml) andwater (1 ml) and LiOH.H₂O (14 mg, 0.33 mmol) was added in one portion.The mixture was stirred at 50° C. for 16 h. The mixture was concentratedunder reduced pressure and acidified to pH=3. Purification bypreparative HPLC afforded3-[3-(4-methyl-1-phenyl-pent-(Z)-ylidene)-2-oxo-2,3-dihydro-indol-1-ylmethyl]-benzoicacid 10 mg. ¹H NMR (300 Hz, CDCl₃): δppm 0.88 (d, 6H), 1.36-1.44 (m,2H), 1.64-1.68 (m, 1H), 3.33-3.38 (m, 2H), 5.04 (s, 2H), 6.01 (d, 1H),6.58-6.61 (m, 2H), 6.96-7.02 (t, 1H), 7.26-7.29 (m, 2H), 7.37 (t, 2H),7.43-7.52 (m, 3H), 7.93 (d, 1H), 8.03 (s, 1H).

Example 823-{3-[1-(4-Chloro-benzyl)-2-methyl-prop-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid

The title compound was prepared in analogy to Example 81 starting from3-{3-[1-(4-chloro-benzyl)-2-methyl-prop-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester. ¹H NMR (300 Hz, CDCl₃): δppm 1.14 (d, 6H), 3.62-3.71(m, 1H), 4.577 (s, 2H), 5.018 (s, 2H), 6.82 (d, 1H), 7.04 (t, 1H),7.21-7.26 (m, 5H), 7.43 (t, 1H), 7.53 (d, 1H), 7.63 (d, 1H), 8.01 (d,1H), 8.07 (s, 1H).

Example 833-{3-[1-(4-Fluoro-phenyl)-ethylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid

But-2-ynoic acid (2-iodo-phenyl)-amide

A mixture of 2-iodo-phenylamine (10 g, 45.7 mmol) and but-2-ynoic acid(4.6 g, 54.8 mmol) in dichloromethane (50 ml) was cooled to 0° C. Then1,3-dicyclohexylcarbodiimide (14 g, 68.6 mmol) was added. After stirringfor 3 hours at room temperature, the mixture was washed with water (20ml). The organic layer was dried over sodium sulfate and concentrated togive the crude product but-2-ynoic acid (2-iodo-phenyl)-amide (13.0 g,100%) as a yellow solid which was used in next step withoutpurification. MS calcd. for C₁₀H₈INO 285.1, obsd. (ESI⁺) [(M+H)⁺] 286.0.

3-{[(2-Iodo-phenyl)-(1-oxo-but-2-ynyl)-amino]-methyl}-benzoic acidmethyl ester

A mixture of but-2-ynoic acid (2-iodo-phenyl)-amide (2.85 g, 10 mmol)and cesium carbonate (4.89 g, 15 mmol) in DMF (20 ml) was stirred for 10minutes. 3-bromomethyl-benzoic acid methyl ester (2.52 g, 11 mmol) wasadded. Then the mixture was stirred for 12 hours at room temperature.After removal of solids, the filtrate was treated with water andextracted with ether. The organic layer was dried over sodium sulfateand concentrated to give the residue which was purified by flashchromatography, eluting with ethyl acetate/hexane= 1:4 to afford theproduct 3-{[(2-iodo-phenyl)-(1-oxo-but-2-ynyl)-amino]-methyl}-benzoicacid methyl ester as yellow solid (3.03, 70%). MS calcd. for C₁₉H₁₆INO₃433.3, obsd. (ESP) [(M+H)⁺] 434.1.

3-{3-[1-(4-Fluoro-phenyl)-ethylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester

A mixture of3-{[(2-iodo-phenyl)-(1-oxo-but-2-ynyl)-amino]-methyl}-benzoic acidmethyl ester (0.5 g, 1.15 mmol), 4-fluorophenylboronic acid (0.32 g, 2.3mmol), tetrakis (triphenylphosphine) palladium (0.13 g, 0.115 mmol) andcopper thiophene-2-carboxylic acid (0.46 g, 2.42 mmol) in THF wasstirred for 5 hours at 60° C. After removal of solvent, the residue waspurified by flash chromatography, eluting with ethyl acetate/hexane= 1:5to afford the product3-{3-[1-(4-fluoro-phenyl)-ethylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester (0.28 g, 60%) as a yellow solid. MS calcd. forC₂₅H₂₀FNO₃ 401.4, obsd. (ESP) [(M+H)⁺] 402.2.

3-{3-[1-(4-Fluoro-phenyl)-ethylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid

A solution of3-{3-[1-(4-fluoro-phenyl)-ethylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester (0.33 g, 0.82 mmol) was dissolved in THF 5 ml. Then asolution of lithium hydroxide (0.35 g, 8.2 mmol) in water (2.0 ml) wasadded. After stirring for 12 hours, the solvent was removed underreduced pressure. The residue was dissolved in 2 ml DMF for preparedHPLC to give3-{3-[1-(4-fluoro-phenyl)-ethylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid as yellow powder (100 mg). ¹H NMR (400 MHz, DMSO-d₆) δppm 2.78 (s,3H) 5.06 (s, 2H) 6.08 (d, J=7.83 Hz, 1H) 6.68 (t, J=7.45 Hz, 1H) 6.92(d, J=7.83 Hz, 1H) 7.11 (t, J=7.45 Hz, 1H) 7.38 (t, J=8.84 Hz, 2H)7.43-7.51 (m, 1H) 7.46 (dd, 7=8.72, 5.68 Hz, 2H) 7.60 (d, J=7.58 Hz, 1H)7.85 (d, J=7.83 Hz, 1H) 7.92 (s, 1H) 13.03 (s, 1H). MS calcd. forC₂₄H₁₈FNO₃ 387.4, obsd. (ESI⁺) [(M+H)⁺] 388.2.

Example 843-{3-[1-(4-Chloro-phenyl)-2-methyl-propylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester

1-Iodo-2-isocyanato-benzene

A solution of 2-iodo-phenylamine (30 g, 0.14 mol) in dichloromethane(800 ml) was added triphosgene (14.6 g, 49.3 mmol) and saturated sodiumbicarbonate (544 ml) at 0° C. The resulted mixture was stirred for 4hours. The organic layer was washed with brine (200 ml) and dried oversodium sulfate. After removal of solvent, the crude product1-iodo-2-isocyanato-benzene (32.3 g, 96%) was obtained as a yellow oilwhich was used in next step without purification.

4-Methyl-pent-2-ynoic acid (2-iodo-phenyl)-amide

3-Methyl-but-1-yne (11 g, 0.16 mol) in THF (100 ml) was added n-BuLi(2.5M in hexane) (59 ml, 0.15 mol) at 0° C. The resulting mixture wasstirred for 30 minutes. Then a solution of 1-iodo-2-isocyanato-benzene(33 g, 0.14 mol) in THF (100 ml) was dropped into the mixture. Afterstirring for 2 hours at 0° C., the mixture was treated with brine (100ml) and extracted with ether (200 ml). The organic layer was dried oversodium sulfate and concentrated to give the crude product4-methyl-pent-2-ynoic acid (2-iodo-phenyl)-amide (38 g, 90%) as a yellowoil which was used in next step without purification. MS calcd. forC₁₂H₁₂INO 313.1, obsd. (ESP) [(M+H)⁺]314.0.

3-{[(2-Iodo-phenyl)-(4-methyl-pent-2-ynoyl)-amino]-methyl}-benzoic acidmethyl ester

A mixture of 4-methyl-pent-2-ynoic acid (2-iodo-phenyl)-amide (21 g,67.1 mmol) and cesium carbonate (33.0 g, 100.7 mmol) in DMF (170 ml) wasstirred for 10 minutes. 3-bromomethyl-benzoic acid methyl ester (16.9 g,73.8 mmol) was added. Then the mixture was stirred for 12 hours at roomtemperature. After removal of the solids, the filtrate was treated withwater and extracted with ether. The organic layer was dried over sodiumsulfate and concentrated to give the residue which was purified by flashchromatography, eluting with ethyl acetate/hexane= 1:4 to afford theproduct3-{[(2-iodo-phenyl)-(4-methyl-pent-2-ynoyl)-amino]-methyl}-benzoic acidmethyl ester as yellow solid (15.9 g, 51%). MS calcd. for C₂₁H₂₀ClNO₃461.3, obsd. (ESP) [(M+H)⁺] 461.9.

3-{3-[1-(4-Chloro-phenyl)-2-methyl-propylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester

A mixture of3-{[(2-iodo-phenyl)-(4-methyl-pent-2-ynoyl)-amino]-methyl}-benzoic acidmethyl ester (0.93 g, 2.02 mmol), 4-chlorophenylboronic acid (0.63 g,4.04 mmol), triphenylphosphine (53 mg, 0.202 mmol), palladium acetate(23 mg, 0.10 mmol) and cesium fluoride (0.92 g, 6.06 mmol) in THF (15ml) was stirred for 3 hours at 60° C. After removal of solvent, theresidue was purified by flash chromatography, eluting with ethylacetate/hexane=1:5 to afford the product3-{3-[1-(4-chloro-phenyl)-2-methyl-propylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester (0.40 g, 44%) as a yellow solid. MS calcd. forC₂₇H₂₄ClNO₃ 445.5, obsd. (ESI⁺) [(M+H)⁺] 446.0. ¹H NMR (400 MHz,DMSO-d₆) δppm 1.10 (d, 7=6.82 Hz, 6H) 3.91 (s, 3H) 4.99 (dt, J=13.71,6.92 Hz, 1H) 5.06 (s, 2H) 5.73 (d, J=7.58 Hz, 1H) 6.62 (t, J=7.71 Hz,1H) 6.73 (d, J=7.83 Hz, 1H) 7.05 (t, J=7.71 Hz, 1H) 7.19 (d, J=8.34 Hz,2H) 7.46 (t, J=7.83 Hz, 1H) 7.55 (d, J=8.08 Hz, 3H) 7.94 (d, J=7.58 Hz,1H) 8.02 (s, 1H) MS calcd. for C₂₇H₂₄ClNO₃ 445.5, obsd. (ESI⁺) [(M+H)⁺]446.0.

Example 853-{3-[2-Methyl-1-phenyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester

The title compound was prepared in analogy to Example 84 starting fromphenylboronic acid (commercially available) and 3-{[(2-iodophenyl)-(4-methyl-pent-2-ynoyl)-amino]-methyl}-benzoic acid methylester. ¹H NMR (CDCl₃, 300 MHz) δppm 8.04 (s, 1H), 7.94 (d, 1H),7.48-7.53 (m, 3H), 7.39 (t, 1H), 7.15 (dd, 2H), 6.99 (t, 1H), 6.59-6.61(d, 1H), 6.55 (t, 1H), 5.59 (d, 2H), 5.00-5.05 (m, 3H), 3.97 (s, 3H),1.11 (s, 3H), 1.09 (s, 3H).

Example 863-{3-[1-(4-Acetyl-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester

The title compound was prepared in analogy to Example 84 starting from4-acetyl-phenylboronic acid (commercially available) and 3-{[(2-iodophenyl)-(4-methyl-pent-2-ynoyl)-amino]-methyl}-benzoic acid methylester. ¹H NMR (CDCl₃, 300 MHz) δppm 8.03-8.11 (m, 4H), 7.94 (d, 1H),7.71 (d, 1H), 7.52 (d, 1H), 7.40 (t, 1H), 7.29 (d, 2H), 7.00 (t, 1H),6.61 (d, 1H), 6.54 (t, 1H), 5.61 (d, H), 5.02-5.07 (m, 3H), 3.90 (s,3H), 2.70 (s, 3H), 1.19 (d, 3H), 1.17 (d, 3H).

Example 873-{3-[1-(4-Chloro-phenyl)-1-cyclohexyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester

The title compound was prepared in analogy to Example 84 starting from4-chloro-phenylboronic acid (commercially available) and3-{[(3-cyclohexyl-propynoyl)-(2-iodo-phenyl)-amino]-methyl}-benzoic acidmethyl ester. ¹H NMR (CDCl₃, 300 MHz) δppm 8.02 (s, 1H), 7.93 (d, 1H),7.47-7.51 (m, 13H), 7.39 (t, 1H), 7.10 (d, 2H), 7.01 (t, 1H), 6.59-6.63(m, 2H), 5.71 (d, 2H), 5.02 (s, 2H), 4.62 (t, 1H), 3.91 (s, 3H),1.44-1.76 (m, 6H), 1.01-1.18 (m, 4H).

Example 883-{3-[2-Methyl-1-(4-trifluoromethyl-phenyl)-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester

The title compound was prepared in analogy to Example 84 starting from4-trifluoromethyl-phenylboronic acid (commercially available) and3-{[(2-iodo phenyl)-(4-methyl-pent-2-ynoyl)-amino]-methyl}-benzoic acidmethyl ester. ¹H NMR (DMSO, 300 MHz) δppm 7.90 (s, 1H), 7.79-7.86 (m,2H), 7.58 (d, 1H), 7.48 (t, 1H), 7.42 (d, 1H), 7.09 (t, 1H), 7.00 (d,1H), 6.89 (d, 1H), 6.65 (t, 1H), 5.65 (d, 1H), 5.03 (s, 2H), 4.84-4.93(m, 1H), 3.57 (s, 3H), 0.96-1.06 (dd, 6H).

Example 893-{3-[1-(4-Chloro-phenyl)-2-hydroxy-2-methyl-prop-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester

The title compound was prepared in analogy to Example 84 starting from4-chloro-phenylboronic acid (commercially available) and3-{[(4-hydroxy-4-methyl-pent-2-ynoyl)-(2-iodo-phenyl)-amino]-methyl}-benzoicacid methyl ester. ¹H NMR (400 MHz, DMSO-d₆) δppm 1.30 (s, 6H) 3.83 (s,3H) 5.14 (s, 2H) 5.43 (d, J=7.58 Hz, 1H) 6.68 (t, J=7.58 Hz, 1H) 7.01(d, J=7.83 Hz, 1H) 7.12 (t, J=7.45 Hz, 1H) 7.27 (d, J=8.34 Hz, 2H) 7.51(t, J=7.71 Hz, 1H) 7.58-7.65 (m, 4H) 7.87 (d, J=7.58 Hz, 1H) 7.97 (s,1H).

Example 903-{3-[1-(4-Cyano-phenyl)-2-hydroxy-2-methyl-prop-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester

The title compound was prepared in analogy to Example 84 starting from4-cyano-phenylboronic acid (commercially available) and3-{[(4-hydroxy-4-methyl-pent-2-ynoyl)-(2-iodo-phenyl)-amino]-methyl}-benzoicacid methyl ester. ¹H NMR (400 MHz, DMSO-d₆) δppm 1.33 (s, 6H) 3.85 (s,3H) 5.15 (s, 2H) 5.35 (d, J=7.83 Hz, 1H) 6.68 (t, J=7.71 Hz, 1H) 7.03(d, J=7.83 Hz, 1H) 7.15 (t, J=7.71 Hz, 1H) 7.48-7.55 (m, 1H) 7.52 (d,J=7.58 Hz, 3H) 7.62 (d, J=7.83 Hz, 1H) 7.89 (d, J=7.83 Hz, 1H) 7.99 (s,1H) 8.05 (d, J=8.34 Hz, 2H).

Example 913-{3-[1-(4-Chloro-phenyl)-2,2-dimethyl-prop-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester

The title compound was prepared in analogy to Example 84 starting from4-chloro-phenylboronic acid (commercially available) and3-{[(4,4-dimethyl-pent-2-ynoyl)-(2-iodo-phenyl)-amino]-methyl}-benzoicacid methyl ester. ¹H NMR (400 MHz, MeOD) δppm 1.38 (s, 9H) 3.86 (s, 3H)4.83 (d, 2H) 6.81 (d, J=7.83 Hz, 1H) 6.99 (d, J=7.83 Hz, 2H) 7.10 (t,J=7.58 Hz, 1H) 7.22 (t, J=7.71 Hz, 1H) 7.33-7.42 (m, 4H) 7.84-7.88 (m,2H) 7.93 (d, J=7.83 Hz, 1H).

Example 923-{3-[1-(4-Cyano-phenyl)-2,2-dimethyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester

The title compound was prepared in analogy to Example 84 starting from4-cyano-phenylboronic acid (commercially available) and3-{[(4,4-dimethyl-pent-2-ynoyl)-(2-iodo-phenyl)-amino]-methyl}-benzoicacid methyl ester. ¹H NMR (400 MHz, DMSO-d₆) δppm 1.35 (s, 9H) 3.84 (s,3H) 5.07 (s, 2H) 5.19 (d, J=7.83 Hz, 1H) 6.56 (t, J=7.71 Hz, 1H) 6.88(d, J=7.83 Hz, 1H) 7.06 (t, J=7.71 Hz, 1H) 7.42 (d, J=8.08 Hz, 2H) 7.50(t, J=7.71 Hz, 1H) 7.59 (d, J=7.58 Hz, 1H) 7.87 (d, J=7.58 Hz, 1H)7.95-8.05 (m, 3H).

Example 933-{3-[1-(4-Chloro-phenyl)-2,2-dimethyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester

The title compound was prepared in analogy to Example 84 starting from4-chloro-phenylboronic acid (commercially available) and3-{[(4,4-dimethyl-pent-2-ynoyl)-(2-iodo-phenyl)-amino]-methyl}-benzoicacid methyl ester. ¹H NMR (400 MHz, DMSO-d₆) δppm 1.36 (s, 9H) 3.84 (s,3H) 5.07 (s, 2H) 5.30 (d, J=7.83 Hz, 1H) 6.57 (t, J=7.83 Hz, 1H) 6.88(d, J=7.83 Hz, 1H) 7.05 (t, J=7.71 Hz, 1H) 7.21 (d, J=8.08 Hz, 2H) 7.51(t, J=7.71 Hz, 1H) 7.57-7.64 (m, 2H) 7.87 (d, J=7.58 Hz, 1H) 7.97 (s,1H).

Example 943-{3-[1-(4-chloro-phenyl)-2-methyl-propylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid

A solution of3-{3-[1-(4-chloro-phenyl)-2-methyl-propylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester (0.40 g, 0.90 mmol) was dissolved in THF 15 ml. Then asolution of lithium hydroxide (0.38 g, 9.0 mmol) in water (3.0 ml) wasadded. After stirring for 12 hours, the solvent was removed underreduced pressure. The residue was dissolved in 2 ml DMF for preparedHPLC to give3-{3-[1-(4-chloro-phenyl)-2-methyl-propylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid as a yellow powder (200 mg). ¹H NMR (400 MHz, DMSO-d₆) δppm 1.00(d, J=6.82 Hz, 6H) 4.90-4.99 (m, 1H) 5.05 (s, 2H) 5.59 (d, J=7.83 Hz,1H) 6.64 (t, J=7.71 Hz, 1H) 6.91 (d, J=7.83 Hz, 1H) 7.10 (t, J=7.71 Hz,1H) 7.27 (d, J=8.34 Hz, 2H) 7.49 (t, J=7.58 Hz, 1H) 7.63 (d, J=8.34 Hz,2H) 7.59 (d, J=7.58 Hz, 1H) 7.85 (d, J=7.58 Hz, 1H) 7.92 (s, 1H) 13.05(s, 1H). MS calcd. for C₂₆H₂₂ClNO₃ 431.5, obsd. (ESI⁺) [(M+H)⁺] 432.0.

Example 953-{3-[1-(4-Cyano-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid

The title compound was prepared in analogy to Example 94 starting from3-{3-[1-(4-cyano-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydroindol-1-ylmethyl}benzoic acid methyl ester. ¹H NMR (400 MHz, DMSO-d₆) δppm 1.01 (d,J=6.82 Hz, 6H) 4.91-5.00 (m, 1H) 5.05 (s, 2H) 5.50 (d, J=7.83 Hz, 1H)6.64 (t, J=7.58 Hz, 1H) 6.93 (d, J=7.83 Hz, 1H) 7.11 (t, J=7.58 Hz, 1H)7.48 (d, J=7.58 Hz, 3H) 7.60 (d, J=7.58 Hz, 1H) 7.85 (d, J=7.33 Hz, 1H)7.93 (s, 1H) 8.05 (d, J=8.08 Hz, 2H) 13.06 (br. s., 1H).

Example 966-{3-[1-(4-Chloro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-pyridine-2-carboxylicacid

The title compound was prepared in analogy to Example 94 starting from6-{3-[1-(4-chloro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1ylmethyl}-pyridine-2-carboxylicacid methyl ester. ¹H NMR (400 MHz, MeOD) δppm 1.06 (d, 6H) 4.92-5.01(m, 1H) 5.23 (s, 2H) 5.74 (d, 1H) 6.64 (t, 1H) 6.87 (d, 1H) 7.08 (t, 1H)7.22 (d, 2H) 7.45 (d, 1H) 7.59 (d, 2H) 7.95 (t, 1H) 8.09 (d, 1H).

Example 976-{3-[1-(4-Cyano-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-pyridine-2-carboxylicacid

The title compound was prepared in analogy to Example 94 starting from6-{3-[1-(4-cyano-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydroindol-1-ylmethyl}-pyridine-2-carboxylicacid methyl ester. ¹H NMR (400 MHz, MeOD) δppm 1.06 (d, 6H) 4.95-5.08(m, 1H) 5.25 (s, 2H) 5.64 (d, 1H) 6.63 (t, 1H) 6.89 (d, 1H) 7.09 (t, 1H)7.46 (d, 3H) 7.90-8.00 (m, 3H) 8.09 (d, 1H).

Example 983-{3-[1-(4-Chloro-phenyl)-2,2-dimethyl-prop-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid

The title compound was prepared in analogy to Example 94 starting from3-{3-[1-(4-chloro-phenyl)-2,2-dimethyl-prop-(Z)ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester. ¹H NMR (400 MHz, DMSO-d₆) δppm 1.32 (s, 9H) 4.86 (s,2H) 6.95 (d, J=7.58 Hz, 1H) 7.04 (d, J=8.59 Hz, 2H) 7.13 (t, 1H) 7.29(t, 1H) 7.38-7.42 (m, 2H) 7.44 (d, J=5.05 Hz, 2H) 7.77-7.84 (m, 2H) 7.88(d, J=7.83 Hz, 1H) 13.01 (s, 1H).

Example 993-{3-[1-(4-Cyano-phenyl)-2,2-dimethyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid

The title compound was prepared in analogy to Example 94 starting from3-{3-[1-(4-cyano-phenyl)-2,2-dimethyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1ylmethyl}-benzoicacid methyl ester. ¹H NMR (400 MHz, DMSO-d₆) δppm 1.35 (s, 9H) 5.06 (s,2H) 5.19 (d, J=7.83 Hz, 1H) 6.57 (t, J=7.45 Hz, 1H) 6.89 (d, J=7.58 Hz,1H) 7.07 (t, J=7.45 Hz, 1H) 7.41-7.51 (m, 3H) 7.56 (d, 1H) 7.84 (d,J=7.58 Hz, 1H) 7.93 (s, 1H) 8.03 (d, J=8.34 Hz, 2H).

Example 1003-{3-[1-(4-Chloro-phenyl)-2,2-dimethyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid

The title compound was prepared in analogy to Example 94 starting from3-{3-[1-(4-chloro-phenyl)-2,2-dimethyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester. ¹H NMR (400 MHz, DMSO-d₆) δppm 1.35 (s, 9H) 5.06 (s,2H) 5.30 (d, J=7.83 Hz, 1H) 6.57 (t, 1H) 6.88 (d, J=7.83 Hz, 1H) 7.06(t, 1H) 7.22 (d, J=8.08 Hz, 2H) 7.49 (t, 1H) 7.54-7.63 (m, 3H) 7.84 (d,1H) 7.93 (s, 1H) 12.97 (s, 1H).

Example 1013-{3-[1-(4-Fluoro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid

The title compound was prepared in analogy to Example 94 starting from3-{3-[1-(4-fluoro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester. ¹H NMR (400 MHz, DMSO-d₆) δppm 1.01 (d, J=6.82 Hz,6H) 4.87-4.99 (m, 1H) 5.05 (s, 2H) 5.54 (d, J=7.83 Hz, 1H) 6.63 (t,J=7.33 Hz, 1H) 6.90 (d, J=7.58 Hz, 1H) 7.09 (d, J=1.01 Hz, 1H) 7.24-7.31(m, 2H) 7.40 (t, J=8.84 Hz, 2H) 7.49 (t, J=7.58 Hz, 1H) 7.59 (d, J=7.58Hz, 1H) 7.85 (d, J=7.83 Hz, 1H) 7.92 (s, 1H) 13.03 (s, 1H).

Example 1026-{3-[1-(4-Fluoro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-pyridine-2-carboxylicacid

The title compound was prepared in analogy to Example 94 starting from6-{3-[1-(4-fluoro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}pyridine-2-carboxylicacid methyl ester. ¹H NMR (400 MHz, DMSO-d₆) δppm 1.01 (d, J=6.82 Hz,6H) 4.86-5.00 (m, 1H) 5.16 (br. s., 2H) 5.56 (d, J=7.83 Hz, 1H) 6.63 (t,J=7.71 Hz, 1H) 6.85 (d, J=7.33 Hz, 1H) 7.06 (t, J=7.58 Hz, 1H) 7.29 (d,J=5.56 Hz, 2H) 7.27 (d, J=5.81 Hz, 1H) 7.41 (t, J=8.72 Hz, 2H) 7.81-7.98(m, 2H).

Example 1033-{3-[2-Methyl-1-pyridin-3-yl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid

The title compound was prepared in analogy to Example 94 starting from3-{3-[2-methyl-1-pyridin-3-yl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester. ¹H NMR (400 MHz, MeOD) δppm 1.13 (t, J=7.71 Hz, 6H)5.01-5.14 (m, 1H) 5.10 (s, 2H) 5.59 (d, J=7.83 Hz, 1H) 6.62 (t, J=7.71Hz, 1H) 6.83 (d, J=7.83 Hz, 1H) 7.11 (t, J=7.71 Hz, 1H) 7.47 (t, J=7.71Hz, 1H) 7.59 (d, J=7.58 Hz, 1H) 7.84 (br. s., 1H) 7.93-8.05 (m, 2H) 7.96(s, 1H) 8.58 (br. s., 1H) 8.85 (br. s., 1H).

Example 1043-{3-[1-(4-Chloro-phenyl)-1-cyclohexyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid

The title compound was prepared in analogy to Example 94 starting from3-{3-[1-(4-chloro-phenyl)-1-cyclohexyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester. ¹H NMR (CDCl₃, 300 MHz) δppm 8.09 (s, 1H), 8.02 (d,1H), 7.57 (d, 1H), 7.41-7.50 (m, 3H), 7.11 (d, 2H), 7.03 (t, 1H),6.60-6.64 (m, 2H), 5.73 (d, 1H), 5.05 (s, 2H), 4.63 (m, 1H), 1.44-1.81(m, 6H), 1.01-1.18 (m, 4H).

Example 1053-{3-[2-Methyl-1-(4-trifluoromethyl-phenyl)-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid

The title compound was prepared in analogy to Example 94 starting from3-{3-[2-methyl-1-(4-trifluoromethyl-phenyl)-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester. ¹H NMR (CDCl₃, 300 MHz) δppm 8.08 (s, 1H), 8.00 (d,1H), 7.77 (d, 2H), 7.58 (d, 1H), 7.44 (t, 1H), 7.31 (d, 2H), 7.03 (t,1H), 6.63 (d, 1H), 6.58 (t, 1H), 5.58 (d, 1H), 5.04-5.08 (m, 3H), 1.16(s, 3H), 1.13 (s, 1H).

Example 1063-{3-[2-Methyl-1-thiophen-3-yl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid

The title compound was prepared in analogy to Example 94 starting from3-{3-[2-methyl-1-thiophen-3-yl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester. ¹H NMR (CDCl₃, 300 MHz) δppm 8.08 (s, 1H), 8.01 (d,1H), 7.77 (d, 2H), 7.58 (d, 1H), 7.44 (t, 1H), 7.31 (d, 2H), 7.03 (t,1H), 6.63 (d, 1H), 6.58 (t, 1H), 5.58 (d, 1H), 5.04-5.08 (m, 3H), 1.10(s, 3H), 1.07 (s, 3H).

Example 1073-{5-Chloro-3-[2-methyl-1-(4-trifluoromethyl-phenyl)-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid

The title compound was prepared in analogy to Example 94 starting from3-{5-chloro-3-[2-methyl-1-(4-trifluoromethylphenyl)-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester. ¹H NMR (300 Hz, CDCl₃): δppm 1.11 (d, 6H), 5.00-5.04(m, 1H), 5.01 (s, 2H), 5.40 (d, 1H), 6.51 (d, 1H), 6.98 (dd, 1H), 7.28(d, 2H), 7.42 (t, 1H), 7.56 (m, 1H), 7.81 (d, 2H), 8.01-8.04m, 2H).

Example 1083-{3-[1-(4-Acetyl-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid

The title compound was prepared in analogy to Example 94 starting from3-{3-[1-(4-acetyl-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester. ¹H NMR (CDCl₃, 300 MHz) δppm 8.00-8.12 (m, 3H), 7.72(d, 1H), 7.57 (d, 1H), 7.44 (t, 1H), 7.29 (d, 2H), 7.02 (t, 1H), 6.62(d, 1H), 6.55 (t, 1H), 5.63 (d, 2H), 5.04 (m, 3H), 2.70 (s, 3H), 1.10(s, 3H), 1.08 (s, 3H).

Example 109N-(3-{3-[1-(4-Chloro-phenyl)-2-methyl-propylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoyl)-methanesulfonamide

A mixture of3-{3-[1-(4-chloro-phenyl)-2-methyl-propylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid (0.22 g, 0.51 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (0.20 g, 1.02 mmol), methylsulfonamide (97 mg, 1.02 mmol),DMAP (12.2 mg, 0.10 mmol) in dichloromethane (20 ml) was stirred for 72hours. The organic solution washed with brine (10 ml) then dried oversodium sulfate. After removal of solvent, the residue was dissolved in 2ml DMF for prepared HPLC to give the productN-(3-{3-[1-(4-chloro-phenyl)-2-methyl-propylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoyl)-methanesulfonamide(100 mg, 38%) as yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δppm 1.21 (d,J=6.82 Hz, 6H) 3.50 (s, 3H) 5.00-5.12 (m, 1H) 5.17 (s, 2H) 5.52 (s, 1H)5.84 (d, J=7.83 Hz, 1H) 6.75 (t, J=7.83 Hz, 1H) 6.85 (d, J=7.83 Hz, 1H)7.17 (t, J=7.20 Hz, 1H) 7.28 (d, J=8.59 Hz, 2H) 7.60 (t, J=7.71 Hz, 1H)7.65 (d, J=8.34 Hz, 2H) 7.70 (d, J=7.83 Hz, 1H) 7.94 (d, J=7.83 Hz, 1H)8.02 (s, 1H). MS calcd. for C₂₇H₂₅ClN₂O₄S 508.5, obsd. (ESI⁺) [(M+H)⁺]509.2.

Example 110N-(3-{3-[1-(4-Chloro-phenyl)-2,2-dimethyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoyl)-methanesulfonamide

The title compound was prepared in analogy to Example 109 starting from3-{3-[1-(4-chloro-phenyl)-2,2-dimethyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid. ¹H NMR (400 MHz, MeOD) δppm 1.44 (s, 9H) 3.11 (s, 3H) 5.05 (s, 2H)5.41 (d, J=7.83 Hz, 1H) 6.52 (t, 1H) 6.74 (d, J=7.58 Hz, 1H) 7.00 (t,1H) 7.12-7.21 (m, 2H) 7.30-7.39 (m, 2H) 7.51-7.60 (m, 2H) 7.89-7.97 (m,1H) 8.04 (s, 1H).

Example 111N-(3-{3-[1-(4-Chloro-phenyl)-2,2-dimethyl-prop-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoyl)-methanesulfonamide

The title compound was prepared in analogy to Example 109 starting from3-{3-[1-(4-chloro-phenyl)-2,2-dimethyl-prop-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid. ¹H NMR (400 MHz, DMSO-d₆) δppm 1.32 (s, 9H) 3.34 (s, 3H) 4.84 (s,2H) 6.93 (d, J=7.83 Hz, 1H) 7.04 (d, J=8.34 Hz, 2H) 7.12 (t, J=7.33 Hz,1H) 7.27 (t, J=7.45 Hz, 1H) 7.37-7.47 (m, 4H) 7.78-7.85 (m, 2H) 7.88 (d,J=8.08 Hz, 1H).

Example 112 Evaluation of AMPK Modulator by Analysis of AMPK and ACCPhosphorylation

This method evaluates endogenous expression and phosphorylation ofAMP-activated protein kinase (AMPK) and acetyl CoA carboxylase (ACC) inL6 cell line using Western blot analysis. It is used to determine thepotency and efficacy of small molecular AMPK modulators. L6 cells (ATCC)are cultured and maintained at DMEM (high glucose, Gibco, BRL) with 10%fetal bovine serum (FBS, Hyclone). In an assay, cells are plated at3×10⁶ per plate in 10 ml on a 10 cm dish and they reach subconfluent of70-80% within 24 hrs. The cells are serum starved overnight prior to betreated with an AMPK modulator. The compound concentration typicallyranges from 0 to 100 uM and treat the cells for 1-4 hrs. Once theincubation is completed, the medium is aspirated and the cell layer isgently rinsed with 2 ml of ice-cold PBS. 500 μl of lysis buffercontaining 150 mM NaCl, 5 mM EDTA, 2 mM EGTA, 25 mM NaF, 2 mM Na₃VO₄, 1mg/ml of Pefabloc, 1% Triton X-100, and a Roche Complete ProteaseInhibitor Tablet is added and incubated on ice for 10 min. The celllysate is harvested and subsequently centrifugated at 12,000 rpm for 10min at 4° C. The supernatant is saved and its protein concentration isdetermined using Quick Start Bradford protein quantification kit(Bio-Rad). 40 jug is loaded for 7.5% SDS-PAGE analysis and subsequentlyblotted to PVDF membrane following a standard procedure. The membrane istreated with a blocking buffer (5% nonfat milk) for 1 h at roomtemperature in agitation. The levels of phospho-AMPK and phospho-ACC aredetermined using phospho-AMPKα(Thr172)(40H9) rabbit mAb (Cell Signaling)and phospho-acetyl CoA carboxylase(Ser79) antibody (Cell Signaling) asprimary antibodies by incubating the blot at 4° C. overnight. The blotsare stripped and re-probed using acetyl CoA carboxylase (C83B10) rabbitmAb (Cell signaling), AMPKα(23A3) rabbit mAb (Cell Signaling), andβ-actin antibody (Cell Signaling) to determine the whole protein levelof ACC, AMPK and β-actin, respectively. Each protein band in a blot isvisualized via ECL Plus Western blotting detection kit (Amersham) andquantified by the scan analysis. The EC₅₀ value, defined as an activatorconcentration that produces half of the maximal activation effect, andEmax, defined as the maximal activation effect at the infinite activatorconcentration, are determined semi-quantitatively and recorded. All thecompounds of formula (I) are active in the foregoing AMPK and ACCphosphorylation assay.

Example 113 Scintillation Proximity Assay Preparation of Enzymes

Recombinant human AMPK α1β1γ1, α2β1γ1 or AMPK α subunit truncationsal(1-335), α1(1-394) and α2(1-394) were constructed, expressed andpurified as described previously (Pang, T., Zhang, Z. S., Gu, M., Qiu,B. Y., Yu, L. F., Cao, P. R., Shao, W., Su, M. B., Li, J. Y., Nan, F.J., and Li, J. (2008)). Rat liver AMPK heterotrimer enzyme was obtainedfrom Upstate (Billerica, Mass., U.S.A.).

Scintillation Proximity Assay

Before the Scintillation Proximity Assay (SPA) assay, 200 nM recombinantAMPK proteins (α1β1γ1, α2β1γ1, α1(1-335), α1(1-394) or α2(1-394)) werefully phosphorylated as described previously (Pang et al., 2008). SPAreactions were performed in 96-well plates at a final volume of 50 μlcontaining 20 mM Tris-HCl pH 7.5, 5 mM MgCl₂, 1 mM DTT, 2 μMbiotin-SAMS, 2 μM ATP, 0.2 μCi/well [γ-³³P]ATP, and various amount ofactivator. Reactions were initiated by the addition of 50 nM recombinantAMPK proteins to the reaction solutions and incubated at 30° C. for 2hr. After that, reactions were terminated by the addition of 40 μl stopsolution containing 80 μg streptavidin-coated SPA beads per well, 50 mMEDTA, 0.1% Triton X-100 in PBS, pH 7.5 and incubated for 1 hr. Finally,a 160 ul suspension solution containing 2.4 M CsCl, 50 mM EDTA, and 0.1%Triton X-100 in PBS (pH 7.5) was added to the reaction solution tosuspend SPA beads completely. SPA signals were determined with a WallacMicroBeta plate counter (PerkinElmer) 30 min later for calculation ofthe amount of product formed. The amount of products formed in 2 hr wasplotted against activator concentrations to determine the effectiveconcentration of the activator (EC50) required for 50% of maximal enzymeactivity. Compounds as described above have EC50 values between 0.5 uMand 50 uM, preferred compounds have EC50 values between 0.5 uM and 10uM, particularly preferred compounds have EC50 values between 0.5 uM and1 uM. These results have been obtained by using the foregoingScintillation Proximity Assay (uM means microMolar).

The EC50 of representative compounds of formula (I) are reported in thefollowing table.

Example No. EC50 (uM) 1 2.21 2 1.49 3 5.61 4 5.25 5 2.3 6 1.51 7 1.54 86.47 9 2.16 10 4.44 11 3.11 12 5.34 13 1.86 14 4.34 15 2.47 16 1.53 172.34 18 5.66 19 1 20 1.76 21 6.07 22 4.13 23 6.97 24 4.82 25 2.73 261.25 27 2.73 28 0.8 29 2.36 30 1.65 31 0.77 32 10.52 33 5.56 34 1.8 352.95 36 3.69 37 4.49 38 2.91 39 1.57 41 4.51 42 4.5 43 3.23 44 1.21 451.89 46 4.02 47 2.38 48 3.15 49 1.75 50 5.89 51 1.42 52 6.55 53 5.89 545.14 55 2.94 56 4.24 57 2.17 58 4.87 59 5.19 60 1.24 61 4.93 62 2.33 633.24 64 6.63 65 3.41 66 2.44 67 1.27 68 2.12 69 2.2 70 4.96 71 4.02 723.3 73 5.14 74 3.17 75 1.84 76 5.14 77 2.58 78 1.6 79 1.69 80 5.8 814.74 82 1.6 85 4.9 86 7.88 87 10.65 88 2.59 104 4.63 105 2.95 106 1.61107 0.66 108 3.25

Example A

A compound of formula (I) can be used in a manner known per se as theactive ingredient for the production of tablets of the followingcomposition:

Per tablet Active ingredient 200 mg Microcrystalline cellulose 155 mgCorn starch 25 mg Talc 25 mg Hydroxypropylmethylcellulose 20 mg 425 mg

Example B

A compound of formula (I) can be used in a manner known per se as theactive ingredient for the production of capsules of the followingcomposition:

Per capsule Active ingredient 100.0 mg Corn starch 20.0 mg Lactose 95.0mg Talc 4.5 mg Magnesium stearate 0.5 mg 220.0 mg

1. A compound of formula (I),

wherein R¹ is selected from the group consisting of: hydrogen, halogen,alkoxy, cyano, haloalkyl, alkylsulfanyl, aminosulfonyl, alkylsulfonyl,haloalkoxy and alkylcarbonyl; R² is selected from the group consistingof: hydrogen, halogen, alkoxy, cyano, haloalkyl, alkylsulfanyl,aminosulfonyl, alkylsulfonyl, haloalkoxy and alkylcarbonyl; R³ isselected from the group consisting of: hydrogen, halogen, alkoxy, cyano,haloalkyl, alkylsulfanyl, aminosulfonyl, alkylsulfonyl, haloalkoxy andalkylcarbonyl; R⁴ is selected from the group consisting of: hydrogen,halogen, alkoxy, cyano, haloalkyl, alkylsulfanyl, aminosulfonyl,alkylsulfonyl, haloalkoxy and alkylcarbonyl; R⁵ is selected from thegroup consisting of: alkyl, hydroxyalkyl, cycloalkyl, phenylalkyl,halophenylalkyl, phenyl, substituted phenyl, thiophenyl and pyridinyl,wherein said substituted phenyl is phenyl substituted with one to threesubstituents independently selected from the group consisting of alkyl,alkoxy, halogen, cyano, haloalkyl, alkylsulfanyl, aminosulfonyl,alkylsulfonyl, haloalkoxy and alkylcarbonyl; R⁶ is selected from thegroup consisting of: alkyl, hydroxyalkyl, cycloalkyl, phenylalkyl,halophenylalkyl, phenyl, substituted phenyl, thiophenyl and pyridinyl,wherein said substituted phenyl is phenyl substituted with one to threesubstituents independently selected from the group consisting of alkyl,alkoxy, halogen, cyano, haloalkyl, alkylsulfanyl, aminosulfonyl,alkylsulfonyl, haloalkoxy and alkylcarbonyl; R⁷ is selected from thegroup consisting of: substituted phenyl, pyridinyl, substitutedpyridinyl, thiazolyl, substituted thiazolyl and carboxy, wherein saidsubstituted phenyl is phenyl substituted with one to three substituentsindependently selected from the group consisting of alkyl, hydroxy,alkoxy, carboxy, alkoxycarbonylalkyl, alkylaminocarbonyl, carboxyalkoxy,alkoxycarbonyl, alkoxycarbonylalkoxy and alkylsulfonylaminocarbonyl, andsaid substituted pyridinyl and said substituted thiazolyl are,respectively, pyridinyl and thiazolyl substituted with alkoxycarbonyl orcarboxy; and n is 0 or 1; or a pharmaceutically acceptable salt or esterthereof; with the provisos that: R⁵ and R⁶ are not both methoxyphenyl atthe same time; and when one of R⁵ and R⁶ is phenyl and the other one isphenyl, methylphenyl or alkoxyphenyl, R⁷ is alkoxycarbonylphenyl.
 2. Acompound according to claim 1, wherein R¹ is selected from the groupconsisting of: hydrogen, halogen and alkoxy.
 3. A compound according toclaim 1, wherein R¹ is selected from the group consisting of: hydrogen,fluoro and chloro.
 4. A compound according to claim 1, wherein R² isselected from the group consisting of: hydrogen, halogen and alkoxy. 5.A compound according to claim 1, wherein R² is hydrogen or fluoro.
 6. Acompound according to claim 1, wherein R³ is selected from the groupconsisting of: hydrogen, halogen and alkoxy.
 7. A compound according toclaim 1, wherein R³ is selected from the group consisting of: hydrogen,fluoro, chloro and methoxy.
 8. A compound according to claim 1, whereinR⁴ is selected from the group consisting of: hydrogen, halogen andalkoxy.
 9. A compound according to claim 1, wherein R⁴ is hydrogen orfluoro.
 10. A compound according to claim 1, wherein R⁵ is selected fromthe group consisting of: alkyl, halophenylalkyl, phenyl, substitutedphenyl, thiophenyl and pyridinyl, wherein said substituted phenyl isphenyl substituted with one to three substituents independently selectedfrom the group consisting of alkyl, alkoxy, halogen, cyano, haloalkyl,alkylsulfanyl, aminosulfonyl, alkylsulfonyl, haloalkoxy andalkylcarbonyl.
 11. A compound according to claim 1, wherein R⁵ ishalophenyl or cyanophenyl.
 12. A compound according to claim 1, whereinR⁵ is chlorophenyl or cyanophenyl.
 13. A compound according to claim 1,wherein R⁶ is selected from the group consisting of: alkyl,hydroxyalkyl, cycloalkyl, phenyl and halophenyl.
 14. A compoundaccording to claim 1, wherein R⁶ is alkyl or phenyl.
 15. A compoundaccording to claim 1, wherein R⁶ is isopropyl or phenyl.
 16. A compoundaccording to claim 1, wherein R⁷ is selected from the group consistingof: substituted phenyl, substituted pyridinyl, substituted thiazolyl andcarboxy, wherein said substituted phenyl is phenyl substituted with oneto three substituents independently selected from the group consistingof alkyl, hydroxy, alkoxy, carboxy, alkoxycarbonylalkyl,alkylaminocarbonyl, carboxyalkoxy, alkoxycarbonyl, alkoxycarbonylalkoxyand alkylsulfonylaminocarbonyl, and said substituted pyridinyl and saidsubstituted thiazolyl are, respectively, pyridinyl and thiazolylsubstituted with alkoxycarbonyl or carboxy.
 17. A compound according toclaim 1, wherein R⁷ is selected from the group consisting of:carboxyphenyl, alkoxycarbonylphenyl and carboxypyridinyl.
 18. A compoundaccording to claim 1, wherein R⁷ is selected from the group consistingof: carboxyphenyl, methoxycarbonylphenyl and carboxypyridinyl.
 19. Acompound according to claim 1 selected from the group consisting of:3-{2-Oxo-3-[1-phenyl-eth-(E)-ylidene]-2,3-dihydro-indol-1-yl}-benzoicacid ethyl ester;(3-{2-Oxo-3-[1-phenyl-eth-(E)-ylidene]-2,3-dihydro-indol-1-yl}-phenyl)-aceticacid methyl ester;2-Methyl-5-{2-oxo-3-[1-phenyl-eth-(E)-ylidene]-2,3-dihydro-indol-1-yl}-benzoicacid methyl ester;[2-Oxo-3-(1-phenyl-ethylidene)-2,3-dihydro-indol-1-yl]-acetic acid;3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester;3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-7-fluoro-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester;3-(3-Benzhydrylidene-2-oxo-2,3-dihydro-indol-1-ylmethyl)-benzoic acidmethyl ester;3-{3-[1-(4-Methoxy-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester;3-{2-Oxo-3-[1-phenyl-1-p-tolyl-meth-(E)-ylidene]-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester;3-{3-[1-(4-Chloro-phenyl)-1-(2-methoxy-phenyl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester;3-{3-[1-(4-Cyano-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester;3-{2-Oxo-3-[1-phenyl-1-(4-trifluoromethyl-phenyl)-meth-(E)-ylidene]-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester;3-{3-[1-(3-Chloro-4-fluoro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester;3-{2-Oxo-3-[1-phenyl-1-(3,4,5-trimethoxy-phenyl)-meth-(E)-ylidene]-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester;3-{3-[1-(3,4-Difluoro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester;3-{3-[1-(3-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester;3-{3-[1-(2-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester;3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-5-fluoro-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester;3-{3-[1-(3,5-Dichloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester;3-{3-[1-(2,3-Dichloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester;4-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester;3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-5-methoxy-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester;3-{3-[1-(2-Bromo-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester;3-{3-[1-(2-Chloro-5-trifluoromethyl-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester;3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-4-fluoro-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester;3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-6-fluoro-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester;3-{3-[1-(3-Bromo-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester;3-{3-[1-(2-Methylsulfanyl-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester;3-{7-Chloro-3-[1-(4-chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-5-fluoro-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester;3-{2-Oxo-3-[1-phenyl-1-(3-trifluoromethyl-phenyl)-meth-(E)-ylidene]-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester;3-{2-Oxo-3-[1-phenyl-1-(4-sulfamoyl-phenyl)-meth-(E)-ylidene]-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester;3-{3-[1-(2-Methanesulfonyl-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester;3-{2-Oxo-3-[1-phenyl-1-thiophen-3-yl-meth-(E)-ylidene]-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester;3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester;3-{3-[1-(4-Chloro-phenyl)-1-(4-trifluoromethyl-phenyl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester;(4-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-phenoxy)-aceticacid ethyl ester;3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-N-isopropyl-benzamide;6-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-nicotinicacid methyl ester;2-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-thiazole-4-carboxylicacid ethyl ester;3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-1-(4-methoxy-benzyl)-1,3-dihydro-indol-2-one;3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-1-(3,4,5-trihydroxy-benzyl)-1,3-dihydro-indol-2-one;3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(Z)-ylidene]-1-(3,4,5-trihydroxy-benzyl)-1,3-dihydro-indol-2-one;3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-1-(4-hydroxy-benzyl)-1,3-dihydro-indol-2-one;3-{3-[1-(4-chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid;3-{3-[1-(4-Fluoro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid;3-{3-[1-(4-Methoxy-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid;3-{3-[1-(4-Chloro-phenyl)-1-(2-methoxy-phenyl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid;3-{2-Oxo-3-[1-phenyl-1-(4-trifluoromethyl-phenyl)-meth-(E)-ylidene]-2,3-dihydro-indol-1-ylmethyl}-benzoicacid;3-{2-Oxo-3-[1-phenyl-1-(2-trifluoromethoxy-phenyl)-meth-(E)-ylidene]-2,3-dihydro-indol-1-ylmethyl}-benzoicacid;3-{3-[1-(3-Chloro-4-fluoro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid;3-{2-Oxo-3-[1-phenyl-1-(3,4,5-trimethoxy-phenyl)-meth-(E)-ylidene]-2,3-dihydro-indol-1-ylmethyl}-benzoicacid;3-{3-[1-(3-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid;3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-5-fluoro-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid;3-{3-[1-(3,5-Dichloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid;3-{3-[1-(2,3-Dichloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid;2-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid;4-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid;3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-5-methoxy-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid;6-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-nicotinicacid;3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-4-fluoro-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid;3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-6-fluoro-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid;3-{3-[1-(2-Methylsulfanyl-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid;3-{2-Oxo-3-[1-phenyl-1-pyridin-3-yl-meth-(E)-ylidene]-2,3-dihydro-indol-1-ylmethyl}-benzoicacid;3-{3-[1-(2-Chloro-5-trifluoromethyl-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid;3-{3-[1-(3,5-Bis-trifluoromethyl-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid;3-{2-Oxo-3-[1-phenyl-1-(3-trifluoromethyl-phenyl)-meth-(E)-ylidene]-2,3-dihydro-indol-1-ylmethyl}-benzoicacid;3-{2-Oxo-3-[1-phenyl-1-(4-sulfamoyl-phenyl)-meth-(E)-ylidene]-2,3-dihydro-indol-1-ylmethyl}-benzoicacid;3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid;3-{3-[1-(4-Chloro-phenyl)-1-(4-trifluoromethyl-phenyl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid;(4-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-phenoxy)-aceticacid;3-{3-[1-(4-Isopropyl-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid;3-{3-[1-(3,4-Difluoro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid;3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-7-fluoro-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid;3-{5-Chloro-3-[1-(4-chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid;3-{3-[1-(2-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid;2-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-thiazole-4-carboxylicacid;3-{3-[4-Methyl-1-phenyl-pent-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester;3-{3-[3,3-Dimethyl-1-phenyl-but-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester;3-{3-[2-(4-Chloro-phenyl)-1-phenyl-eth-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester;3-{3-[3,3-Dimethyl-1-phenyl-but-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester;3-{3-[4-Methyl-1-phenyl-pent-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid;3-{3-[1-(4-Chloro-benzyl)-2-methyl-prop-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid;3-{3-[1-(4-Fluoro-phenyl)-eth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}benzoicacid;3-{3-[1-(4-Chloro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester;3-{3-[2-Methyl-1-phenyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester;3-{3-[1-(4-Acetyl-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester;3-{3-[1-(4-Chloro-phenyl)-1-cyclohexyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester;3-{3-[2-Methyl-1-(4-trifluoromethyl-phenyl)-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester;3-{3-[1-(4-Chloro-phenyl)-2-hydroxy-2-methyl-prop-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester;3-{3-[1-(4-Cyano-phenyl)-2-hydroxy-2-methyl-prop-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester;3-{3-[1-(4-Chloro-phenyl)-2,2-dimethyl-prop-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester;3-{3-[1-(4-Cyano-phenyl)-2,2-dimethyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester;3-{3-[1-(4-Chloro-phenyl)-2,2-dimethyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid methyl ester;3-{3-[1-(4-Chloro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid;3-{3-[1-(4-Cyano-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid;6-{3-[1-(4-Chloro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-pyridine-2-carboxylicacid;6-{3-[1-(4-Cyano-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-pyridine-2-carboxylicacid;3-{3-[1-(4-Chloro-phenyl)-2,2-dimethyl-prop-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid;3-{3-[1-(4-Cyano-phenyl)-2,2-dimethyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid;3-{3-[1-(4-Chloro-phenyl)-2,2-dimethyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid;3-{3-[1-(4-Fluoro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid;6-{3-[1-(4-Fluoro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-pyridine-2-carboxylicacid;3-{3-[2-Methyl-1-pyridin-3-yl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid;3-{3-[1-(4-Chloro-phenyl)-1-cyclohexyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid;3-{3-[2-Methyl-1-(4-trifluoromethyl-phenyl)-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid;3-{3-[2-Methyl-1-thiophen-3-yl)-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid;3-{5-Chloro-3-[2-methyl-1-(4-trifluoromethyl-phenyl)-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid;3-{3-[1-(4-Acetyl-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid;N-(3-{3-[1-(4-Chloro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoyl)-methanesulfonamide;N-(3-{3-[1-(4-Chloro-phenyl)-2,2-dimethyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoyl)-methanesulfonamide;andN-(3-{3-[1-(4-Chloro-phenyl)-2,2-dimethyl-prop-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoyl)-methanesulfonamide;or a pharmaceutically acceptable salt or ester thereof.
 20. A compoundaccording to claim 1 selected from the group consisting of:3-{3-[1-(4-Chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid;3-{3-[1-(4-Chloro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid;3-{3-[1-(4-Cyano-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoicacid;6-{3-[1-(4-Chloro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-pyridine-2-carboxylicacid; and6-{3-[1-(4-Cyano-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-pyridine-2-carboxylicacid; or a pharmaceutically acceptable salt or ester thereof.
 21. Apharmaceutical composition comprising a compound according to claim 1and a therapeutically inert carrier.